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Ref Type

Journal Article

PMID

(30925164)

Authors

Adamovich AI, Banerjee T, Wingo M, Duncan K, Ning J, Martins Rodrigues F, Huang KL, Lee C, Chen F, Ding L, Parvin JD

Title

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PLoS genetics	15	3	2019 03	e1008049	PLoS Genet

URL

Abstract Text

The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.

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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
BARD1	NCBI			BARD1, BRCA1 associated RING domain 1, forms a heterodimer with Brca1, which functions as an E3 ubiquitin ligase and mediator of DNA repair through homology-directed repair (HDR) (PMID: 8944023, PMID: 30925164) and centrosome regulation (PMID: 29858377). Germline mutations in BARD1 are associated with increased susceptibility to breast and ovarian cancers (PMID: 21344236), somatic mutations are highest in colon and endometrial cancers (PMID: 27283171) and BARD1 has also been implicated in neuroblastoma (PMID: 32047556).	Tumor suppressor

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Showing 1 to 117 of 117 entries

Gene	Variant	Impact	Protein Effect	Variant Description
BARD1	P24fs	frameshift	loss of function - predicted	BARD1 P24fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 24 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). P24fs has not been biochemically characterized however, due to the effects of other truncation mutations downstream of P24 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	E27Q	missense	unknown	BARD1 E27Q lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). E27Q results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	G32V	missense	unknown	BARD1 G32V lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). G32V results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	W34R	missense	loss of function	BARD1 W34R lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). W34R confers a loss of function to Bard1 as demonstrated by decreased homology-directed DNA repair activity (PMID: 30925164, PMID: 26350354) and loss of Brca1 binding in culture (PMID: 26350354).
BARD1	A40V	missense	no effect - predicted	BARD1 A40V lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). A40V results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture in one study (PMID: 30925164), and demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture in another study (PMID: 39387837), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	L44R	missense	loss of function	BARD1 L44R lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). L44R confers a loss of function on the Bard1 protein, as demonstrated by loss of homology-directed DNA repair activity and loss of Brca1 binding in cell culture (PMID: 11773071, PMID: 30925164).
BARD1	C53W	missense	loss of function	BARD1 C53W lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). C53W confers a loss of function to the Bard1 protein as demonstrated by loss of nucleosome binding and ubiquitination of histone H2A in in vitro assays (PMID: 29367421), and reduced transcriptional repression of the estrogen metabolism genes Cyp1a1 and Cyp3a4 (PMID: 29367421) and decreased homology-directed DNA repair activity in cultured cells (PMID: 30925164).
BARD1	T54A	missense	unknown	BARD1 T54A lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). T54A results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	C62S	missense	no effect - predicted	BARD1 C62S lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). C62S demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in cell culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	E67K	missense	no effect - predicted	BARD1 E67K lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). E67K demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	I69M	missense	no effect - predicted	BARD1 I69M lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). I69M demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	C71Y	missense	loss of function	BARD1 C71Y lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). C71Y confers a loss of function to the Bard1 protein as demonstrated by loss of nucleosome binding and ubiquitination of histone H2A in in vitro assays (PMID: 29367421), and reduced transcriptional repression of the estrogen metabolism genes Cyp1a1 and Cyp3a4 (PMID: 29367421) and decreased homology-directed DNA repair activity in cultured cells (PMID: 30925164).
BARD1	P84S	missense	unknown	BARD1 P84S lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). P84S results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V85L	missense	no effect - predicted	BARD1 V85L lies within the RING-type zinc finger domain and BRCA1-interacting region of the Bard1 protein (UniProt.org). V85L demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	N98S	missense	no effect - predicted	BARD1 N98S lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). N98S demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S103N	missense	no effect - predicted	BARD1 S103N lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). S103N demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	M104I	missense	no effect - predicted	BARD1 M104I lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). M104I demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164, PMID: 39387837), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S109R	missense	no effect - predicted	BARD1 S109R lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). S109R demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	R112Q	missense	unknown	BARD1 R112Q lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). R112Q results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	H116Y	missense	unknown	BARD1 H116Y lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). H116Y results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	N118S	missense	no effect - predicted	BARD1 N118S lies within the BRCA1-interacting region of the Bard1 protein (UniProt.org). N118S demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	K140N	missense	unknown	BARD1 K140N lies within the Rad51-interacting domain of the Bard1 protein (PMID: 28976962). K140N results in decreased binding to Rad51 and failure to carry out Rad51-mediated DNA strand invasion (PMID: 28976962), but displays homology-directed DNA repair activity similar to wild-type Bard1 in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S142*	nonsense	loss of function - predicted	BARD1 S142* results in a premature truncation of the Bard1 protein at amino acid 142 of 777 (UniProt.org). S142* has not been biochemically characterized however, due to the effects of other truncation mutations downstream of S142 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	W146C	missense	unknown	BARD1 W146C lies within the Rad51-interacting domain of the Bard1 protein (PMID: 28976962). W146C retains the ability to bind Brca1 (PMID: 26350354), but results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S151N	missense	no effect - predicted	BARD1 S151N lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). S151N demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	V154fs	frameshift	loss of function	BARD1 V154fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 154 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). V154fs results in a loss of Bard1 protein expression and decreased homology-directed DNA repair activity in cell culture (PMID: 30925164).
BARD1	Q164*	nonsense	loss of function - predicted	BARD1 Q164* results in a premature truncation of the Bard1 protein at amino acid 164 of 777 (UniProt.org). Q164* has not been biochemically characterized however, due to the effects of other truncation mutations downstream of Q164 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	Y180fs	frameshift	loss of function - predicted	BARD1 Y180fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 180 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). Y180fs has not been biochemically characterized however, due to the effects of other truncation mutations downstream of Y180 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	D190N	missense	no effect - predicted	BARD1 D190N lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). D190N demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	D190Y	missense	no effect - predicted	BARD1 D190Y lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). D190Y demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	R194K	missense	no effect - predicted	BARD1 R194K lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). R194K demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	G203*	nonsense	loss of function - predicted	BARD1 G203* results in a premature truncation of the Bard1 protein at amino acid 203 of 777 (UniProt.org). G203* results in loss of binding to Nfkb1 p50 in cell culture (PMID: 33024116), and due to the effects of other truncation mutations downstream of G203 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	K209Efs*5	frameshift	loss of function - predicted	BARD1 K209Efs5 indicates a shift in the reading frame starting at amino acid 209 and terminating 5 residues downstream causing a premature truncation of the 777 amino acid Bard1 protein (UniProt.org). K209Efs5 has not been biochemically characterized however, due to the effects of other truncation mutations downstream of K209 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	E223G	missense	no effect - predicted	BARD1 E223G lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). E223G demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	D230E	missense	no effect - predicted	BARD1 D230E lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). D230E demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	L239Q	missense	no effect - predicted	BARD1 L239Q lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). L239Q has been associated with increased loss of heterozygosity (LOH) in patient samples, but demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S241C	missense	no effect - predicted	BARD1 S241C lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). S241C demonstrates homology-directed DNA repair activity (PMID: 30925164, PMID: 33623049), subcellular localization, genome stability, and ubiquitin ligase activity similar to wild-type Bard1 in culture (PMID: 33623049), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	I249V	missense	no effect - predicted	BARD1 I249V lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). I249V demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	I258T	missense	no effect - predicted	BARD1 I258T lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). I258T demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S279P	missense	unknown	BARD1 S279P does not lie within any known functional domains of the Bard1 protein (UniProt.org). S279P results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	E287*	nonsense	loss of function - predicted	BARD1 E287* results in a premature truncation of the Bard1 protein at amino acid 287 of 777 (UniProt.org). E287* has not been biochemically characterized however, due to the effects of other truncation mutations downstream of E287 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	K321Nfs*21	frameshift	loss of function - predicted	BARD1 K321Nfs21 indicates a shift in the reading frame starting at amino acid 321 and terminating 21 residues downstream causing a premature truncation of the 777 amino acid Bard1 protein (UniProt.org). K321Nfs21 has not been biochemically characterized however, due to the effects of other truncation mutations downstream of K321 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	R322H	missense	no effect - predicted	BARD1 R322H does not lie within any known functional domains of the Bard1 protein (UniProt.org). R322H demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	N326D	missense	no effect - predicted	BARD1 N326D does not lie within any known functional domains of the Bard1 protein (UniProt.org). N326D demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	N326S	missense	no effect - predicted	BARD1 N326S does not lie within any known functional domains of the Bard1 protein (UniProt.org). N326S demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S339N	missense	unknown	BARD1 S339N does not lie within any known functional domains of the Bard1 protein (UniProt.org). S339N results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S339T	missense	unknown	BARD1 S339T does not lie within any known functional domains of the Bard1 protein (UniProt.org). S339T has been associated with increased loss of heterozygosity (LOH) in patient samples and results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S342N	missense	unknown	BARD1 S342N does not lie within any known functional domains of the Bard1 protein (UniProt.org). S342N results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	T343I	missense	unknown	BARD1 T343I does not lie within any known functional domains of the Bard1 protein (UniProt.org). T343I has been associated with increased loss of heterozygosity (LOH) in patient samples and results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	T351M	missense	unknown	BARD1 T351M does not lie within any known functional domains of the Bard1 protein (UniProt.org). T351M results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	N356I	missense	unknown	BARD1 N356I does not lie within any known functional domains of the Bard1 protein (UniProt.org). N356I retains the ability to bind Brca1 (PMID: 26350354), but results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	E361D	missense	no effect - predicted	BARD1 E361D does not lie within any known functional domains of the Bard1 protein (UniProt.org). E361D demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S389C	missense	unknown	BARD1 S389C does not lie within any known functional domains of the Bard1 protein (UniProt.org). S398C results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R406*	nonsense	loss of function - predicted	BARD1 R406* results in a premature truncation of the Bard1 protein at amino acid 406 of 777 (UniProt.org). R406* has not been biochemically characterized however, due to the effects of other truncation mutations downstream of R406 (PMID: 31371347, PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	R406G	missense	unknown	BARD1 R406G does not lie within any known functional domains of the Bard1 protein (UniProt.org). R406G results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R406Q	missense	unknown	BARD1 R406Q does not lie within any known functional domains of the Bard1 protein (UniProt.org). R406Q results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	I434F	missense	unknown	BARD1 I434F lies within ANK repeat 1 of the Bard1 protein (UniProt.org). I434F results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	A435V	missense	no effect - predicted	BARD1 A435V lies within ANK repeat 1 of the Bard1 protein (UniProt.org). A435V demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	L447C	missense	no effect - predicted	BARD1 L447C lies within ANK repeat 1 of the Bard1 protein (UniProt.org). L447C demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	N450H	missense	no effect - predicted	BARD1 N450H lies within ANK repeat 1 of the Bard1 protein (UniProt.org). N450H has been associated with increased loss of heterozygosity (LOH) in patient samples, but results in homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	G451fs	frameshift	loss of function - predicted	BARD1 G451fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 451 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). G451fs has been associated with increased loss of heterozygosity (LOH) in patient samples and results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	A460T	missense	loss of function	BARD1 A460T lies within ANK repeat 2 of the Bard1 protein (UniProt.org). A460T results in decreased homology-directed DNA repair activity, leads to increased sensitivity to DNA damaging agents in cell culture (PMID: 30925164).
BARD1	L465F	missense	loss of function - predicted	BARD1 L465F lies within ANK repeat 2 of the Bard1 protein (UniProt.org). L465F results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	L480S	missense	loss of function - predicted	BARD1 L480S lies within ANK repeat 2 of the Bard1 protein (UniProt.org). L480S results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	H483R	missense	unknown	BARD1 H483R lies within ANK repeat 2 of the Bard1 protein (UniProt.org). H483R results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	N488S	missense	unknown	BARD1 N488S lies within ANK repeat 2 of the Bard1 protein (UniProt.org). N488S results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	H506R	missense	unknown	BARD1 H506R lies within ANK repeat 3 of the Bard1 protein (UniProt.org). H506R results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V507A	missense	no effect - predicted	BARD1 V507A lies within ANK repeat 3 of the Bard1 protein (UniProt.org). V507A demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	V507M	missense	no effect - predicted	BARD1 V507M lies within ANK repeat 3 of the Bard1 protein (UniProt.org). V507M results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), but leads to similar genome stability, ubiquitin-conjugation, Brca1 and Rad51 foci formation, and DNA damage response as wild-type Bard1 in cultured cells, and is not transforming in Tp53-null cells in a mouse model (PMID: 33623049), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	V510A	missense	unknown	BARD1 V510A lies within ANK repeat 3 of the Bard1 protein (UniProt.org). V510A results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	A518V	missense	unknown	BARD1 A518V lies within ANK repeat 3 of the Bard1 protein (UniProt.org). A518V results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V523A	missense	unknown	BARD1 V523A lies within ANK repeat 3 of the Bard1 protein (UniProt.org). V523A has been associated with increased loss of heterozygosity (LOH) in patient samples, results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V523I	missense	unknown	BARD1 V523I lies within ANK repeat 3 of the Bard1 protein (UniProt.org). V523I results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	P530L	missense	loss of function - predicted	BARD1 P530L lies within ANK repeat 4 of the Bard1 protein (UniProt.org). P530L results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	Y533F	missense	unknown	BARD1 Y533F lies within degenerate ANK repeat 4 of the Bard1 protein (UniProt.org). Y533F results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	K540N	missense	unknown	BARD1 K540N lies within degenerate ANK repeat 4 of the Bard1 protein (UniProt.org). K540N results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S551*	nonsense	loss of function - predicted	BARD1 S551* results in a premature truncation of the Bard1 protein at amino acid 551 of 777 (UniProt.org). S551* results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	H556D	missense	unknown	BARD1 H556D lies within the flexible linker region of the Bard1 protein (UniProt.org). H556D results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S558P	missense	unknown	BARD1 S558P lies within the flexible linker region of the Bard1 protein (UniProt.org). S558P results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	Q564*	nonsense	loss of function	BARD1 Q564* results in a premature truncation of the Bard1 protein at amino acid 564 of 777 (UniProt.org). Q564* confers a loss of function to Bard1 as demonstrated by decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), telomere abnormalities in patient cells, and increased sensitivity to olaparib and cisplatin treatment in cultured cells (PMID: 37688570).
BARD1	Q564H	missense	loss of function	BARD1 Q564H lies within BRCT domain 1 of the Bard1 protein (UniProt.org). Q564H results in decreased Tp53 protein stability, loss of growth inhibition and apoptosis in cell culture (PMID: 16061562) and a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164).
BARD1	R565C	missense	loss of function	BARD1 R565C lies within BRCT domain 1 of the Bard1 protein (UniProt.org). R565C confers a loss of function to Bard1 as demonstrated by decreased homology-directed DNA repair activity in cell culture (PMID: 30925164, PMID: 39387837), altered subcellular localization and decreased DNA repair after irradiation, decreased interaction with Brca1, and increased sensitivity to cisplatin and olaparib treatment in culture (PMID: 39387837).
BARD1	R565H	missense	unknown	BARD1 R565H lies within BRCT domain 1 of the Bard1 protein (UniProt.org). R565H results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	G574D	missense	unknown	BARD1 G574D lies within BRCT domain 1 of the Bard1 protein (UniProt.org). G574D results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S575N	missense	unknown	BARD1 S575N lies within BRCT domain 1 of the Bard1 protein (UniProt.org). S575N results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	T598I	missense	loss of function - predicted	BARD1 T598I lies within BRCT domain 1 of the Bard1 protein (UniProt.org). T598I results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	D612V	missense	no effect - predicted	BARD1 D612V lies within BRCT domain 1 of the Bard1 protein (UniProt.org). D612V demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	S616N	missense	no effect - predicted	BARD1 S616N lies within BRCT domain 1 of the Bard1 protein (UniProt.org). S616N demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture (PMID: 30925164), and therefore, is predicted to have no effect on Bard1 protein function.
BARD1	M621I	missense	unknown	BARD1 M621I lies within BRCT domain 1 of the Bard1 protein (UniProt.org). M621I results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	G623E	missense	loss of function	BARD1 G623E lies within BRCT domain 1 of the Bard1 protein (UniProt.org). G623E confers a loss of function to the Bard1 protein as demonstrated by loss of binding to Brca1 (PMID: 26350354) and decreased homology-directed DNA repair activity in cell culture (PMID: 30925164).
BARD1	L625I	missense	unknown	BARD1 L625I lies within BRCT domain 1 of the Bard1 protein (UniProt.org). L625I results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	N626S	missense	unknown	BARD1 N626S lies within BRCT domain 1 of the Bard1 protein (UniProt.org). N626S results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R641Q	missense	no effect - predicted	BARD1 R641Q lies within BRCT domain 1 of the Bard1 protein (UniProt.org). R641Q results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture in one study (PMID: 30925164), and demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture in another study (PMID: 39387837), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R642G	missense	unknown	BARD1 R642G lies within BRCT domain 1 of the Bard1 protein (UniProt.org). R642G results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	E652fs	frameshift	loss of function - predicted	BARD1 E652fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 652 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). E652fs has not been biochemically characterized however, due to the effects of other truncation mutations downstream of E652 (PMID: 30925164, PMID: 31371347), is predicted to lead to a loss of Bard1 protein function.
BARD1	G656R	missense	unknown	BARD1 G656R does not lie within any known functional domains of the Bard1 protein (UniProt.org). G656R results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R658C	missense	unknown	BARD1 R658C does not lie within any known functional domains of the Bard1 protein (UniProt.org). R658C demonstrates effects on Tp53 stability, cell growth and apoptosis (PMID: 16061562), and homology-directed DNA repair activity similar to wild-type Bard1 in one study (PMID: 39387837), but does not bind to or stabilize Nfkb1 p50 (PMID: 33024116), and results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	S660R	missense	loss of function - predicted	BARD1 S660R does not lie within any known functional domains of the Bard1 protein (UniProt.org). S660R results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	R664T	missense	unknown	BARD1 R664T does not lie within any known functional domains of the Bard1 protein (UniProt.org). R664T results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	F677L	missense	unknown	BARD1 F677L lies within BRCT domain 2 of the Bard1 protein (UniProt.org). F677L results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	G681fs	frameshift	loss of function - predicted	BARD1 G681fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 681 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). G681fs has not been biochemically characterized however, due to the effects of other truncation mutations downstream of G681 (PMID: 30925164, PMID: 31371347), is predicted to lead to a loss of Bard1 protein function.
BARD1	I692T	missense	unknown	BARD1 I692T lies within BRCT domain 2 of the Bard1 protein (UniProt.org). I692T results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V695I	missense	unknown	BARD1 V695I lies within BRCT domain 2 of the Bard1 protein (UniProt.org). V695I results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V695L	missense	unknown	BARD1 V695L lies within BRCT domain 2 of the Bard1 protein (UniProt.org). The functional effect of V695L is conflicting, as it demonstrates homology-directed DNA repair activity similar to wild-type Bard1 in culture in one study (PMID: 17848578), but decreased homology-directed DNA repair activity in another study (PMID: 30925164), and results in reduced growth inhibition and apoptosis (PMID: 16061562), and reduced Ola1 interaction, centrosomal amplification and localization of Bard1 in cell culture (PMID: 29858377), and decreased ability to activate Ola1 in an in vitro assay (PMID: 35134491).
BARD1	G698D	missense	loss of function - predicted	BARD1 G698D lies within BRCT domain 2 of the Bard1 protein (UniProt.org). G698D results in decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), and therefore, is predicted to lead to a loss of Bard1 protein function.
BARD1	P707S	missense	loss of function	BARD1 P707S lies within BRCT domain 2 of the Bard1 protein (UniProt.org). P707S results in decreased homology-directed DNA repair activity compared to wild-type Bard1, leading to increased sensitivity to DNA damaging agents in cell culture (PMID: 30925164).
BARD1	V713M	missense	unknown	BARD1 V713M lies within BRCT domain 2 of the Bard1 protein (UniProt.org). V713M results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	T719A	missense	unknown	BARD1 T719A lies within BRCT domain 2 of the Bard1 protein (UniProt.org). T719A results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	A721T	missense	unknown	BARD1 A721T lies within BRCT domain 2 of the Bard1 protein (UniProt.org). A721T results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	A724V	missense	unknown	BARD1 A724V lies within BRCT domain 2 of the Bard1 protein (UniProt.org). A724V results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	Q730*	nonsense	loss of function - predicted	BARD1 Q730* results in a premature truncation of the Bard1 protein at amino acid 730 of 777 (UniProt.org). Q730* has not been biochemically characterized however, due to the effects of other truncation mutations downstream of Q730 (PMID: 30925164), is predicted to lead to a loss of Bard1 protein function.
BARD1	R731C	missense	unknown	BARD1 R731C lies within BRCT domain 2 of the Bard1 protein (UniProt.org). R731C results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R731G	missense	unknown	BARD1 R731G lies within BRCT domain 2 of the Bard1 protein (UniProt.org). R731G results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	R731H	missense	unknown	BARD1 R731H lies within BRCT domain 2 of the Bard1 protein (UniProt.org). R731H results in a decrease of homology-directed DNA repair activity that is not statistically significant in cell culture (PMID: 30925164), and therefore, its effect on Bard1 protein function is unknown.
BARD1	G753D	missense	loss of function	BARD1 G753D lies within BRCT domain 2 of the Bard1 protein (UniProt.org). G753D results in decreased homology-directed DNA repair activity compared to wild-type Bard1, leading to increased sensitivity to DNA damaging agents in cell culture (PMID: 30925164).
BARD1	S761N	missense	unknown	BARD1 S761N lies within BRCT domain 2 of the Bard1 protein (UniProt.org). The functional effect of S761N is conflicting, as it demonstrates homology-directed DNA repair activity similar to wild-type Bard1, but also results in a loss of growth inhibition and apoptosis in cell culture (PMID: 17848578, PMID: 16061562), reduced association with Ola1 in an in vitro assay (PMID: 29858377), decreased homology-directed DNA repair activity (PMID: 30925164), and does not bind to or stabilize Nfkb1 p50 in cell culture (PMID: 33024116), and therefore, its effect on Bard1 protein function is unknown.
BARD1	V767fs	frameshift	loss of function	BARD1 V767fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 767 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). V767fs results in decreased homology-directed DNA repair activity, leading to increased sensitivity to DNA damaging agents in cell culture (PMID: 30925164).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BARD1 A460T	cervical cancer	sensitive	Cisplatin	Preclinical - Cell culture	Actionable	In a preclinical study, cisplatin treatment of HeLa cells expressing Bard1 A460T were more sensitive than wild-type Bard1 expressing cells, as demonstrated by decreased colony formation (PMID: 30925164).	30925164
BARD1 G753D	cervical cancer	sensitive	Cisplatin	Preclinical - Cell culture	Actionable	In a preclinical study, cisplatin treatment of HeLa cells expressing Bard1 G753D were more sensitive than wild-type Bard1 expressing cells, as demonstrated by decreased colony formation (PMID: 30925164).	30925164
BARD1 P707S	cervical cancer	sensitive	Cisplatin	Preclinical - Cell culture	Actionable	In a preclinical study, cisplatin treatment of HeLa cells expressing Bard1 P707S were more sensitive than wild-type Bard1 expressing cells, as demonstrated by decreased colony formation (PMID: 30925164).	30925164
BARD1 V767fs	cervical cancer	sensitive	Cisplatin	Preclinical - Cell culture	Actionable	In a preclinical study, cisplatin treatment of HeLa cells expressing Bard1 P707S were more sensitive than wild-type Bard1 expressing cells, as demonstrated by decreased colony formation (PMID: 30925164).	30925164

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