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| Gene Symbol | MLH1 | ||||||||||
| Synonyms | COCA2 | FCC2 | hMLH1 | HNPCC | HNPCC2 | LYNCH2 | MLH-1 | MMRCS1 | ||||||||||
| Gene Description | MLH1, mutL homolog 1, is a tumor suppressor (PMID: 30562755) that dimerizes with Pms2 to form a component of the DNA mismatch repair (MMR) system (PMID: 16873062), and is associated with microsatellite instability (MSI) (PMID: 30121009) and genomic stability (PMID: 31747945). MLH1 promoter hypermethylation, resulting in Mlh1 deficiency, is frequently associated with sporadic colorectal, gastric, and esophageal cancers (PMID: 23555617, PMID: 21988782, PMID: 28224663, PMID: 28454461), and germline MLH1 mutations are associated with Lynch (Hereditary Nonpolyposis Colorectal Cancer) syndrome (PMID: 15528792). | ||||||||||
| ACMG Incidental List v3.0: |
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| Molecular Profile | Protein Effect | Treatment Approaches |
|---|---|---|
| MLH1 A111P | loss of function | |
| MLH1 A111V | loss of function | |
| MLH1 A120S | unknown | |
| MLH1 A128P | loss of function | |
| MLH1 A160V | no effect - predicted | |
| MLH1 A20V | unknown | |
| MLH1 A210T | unknown | |
| MLH1 A21E | unknown | |
| MLH1 A21V | loss of function - predicted | |
| MLH1 A281V | no effect - predicted | |
| MLH1 A29S | no effect | |
| MLH1 A31C | loss of function - predicted | |
| MLH1 A410T | unknown | |
| MLH1 A42V | unknown | |
| MLH1 A441T | no effect - predicted | |
| MLH1 A492T | loss of function - predicted | |
| MLH1 A539D | loss of function - predicted | |
| MLH1 A541Dfs*50 | loss of function - predicted | |
| MLH1 A586D | loss of function - predicted | |
| MLH1 A586P | loss of function | |
| MLH1 A589D | unknown | |
| MLH1 A619P | loss of function | |
| MLH1 A681T | unknown | |
| MLH1 A92T | unknown | |
| MLH1 C233R | unknown | |
| MLH1 C39R | loss of function - predicted | |
| MLH1 C77R | loss of function | |
| MLH1 C77Y | loss of function - predicted | |
| MLH1 D132H | unknown | |
| MLH1 D304G | loss of function - predicted | |
| MLH1 D304V | loss of function | |
| MLH1 D41G | loss of function - predicted | |
| MLH1 D41H | loss of function | |
| MLH1 D41N | unknown | |
| MLH1 D41Y | unknown | |
| MLH1 D450Ifs*41 | loss of function - predicted | |
| MLH1 D485E | unknown | |
| MLH1 D601G | no effect - predicted | |
| MLH1 D631H | unknown | |
| MLH1 D63E | loss of function | |
| MLH1 D63N | loss of function - predicted | |
| MLH1 D72Y | unknown | |
| MLH1 D737V | unknown | |
| MLH1 D748A | no effect - predicted | |
| MLH1 del | loss of function | |
| MLH1 del exon4 | unknown | |
| MLH1 del exon5 | unknown | |
| MLH1 E102* | loss of function - predicted | |
| MLH1 E102D | loss of function - predicted | |
| MLH1 E102K | loss of function | |
| MLH1 E13* | loss of function - predicted | |
| MLH1 E172K | unknown | |
| MLH1 E178fs | loss of function - predicted | |
| MLH1 E199K | unknown | |
| MLH1 E199Q | no effect - predicted | |
| MLH1 E227* | loss of function - predicted | |
| MLH1 E234G | loss of function - predicted | |
| MLH1 E23D | loss of function - predicted | |
| MLH1 E268G | no effect - predicted | |
| MLH1 E313* | loss of function - predicted | |
| MLH1 E319K | unknown | |
| MLH1 E34* | loss of function - predicted | |
| MLH1 E37K | loss of function - predicted | |
| MLH1 E460A | no effect | |
| MLH1 E523D | no effect - predicted | |
| MLH1 E578G | unknown | |
| MLH1 E605del | unknown | |
| MLH1 E633Kfs*4 | loss of function - predicted | |
| MLH1 E633_E663del | loss of function | |
| MLH1 E663A | loss of function - predicted | |
| MLH1 E663D | unknown | |
| MLH1 E663G | no effect | |
| MLH1 E703A | unknown | |
| MLH1 E71del | loss of function | |
| MLH1 E754Q | unknown | |
| MLH1 F530Lfs*5 | loss of function - predicted | |
| MLH1 F80V | loss of function | |
| MLH1 G101D | loss of function | |
| MLH1 G101S | loss of function - predicted | |
| MLH1 G101V | loss of function | |
| MLH1 G244D | loss of function - predicted | |
| MLH1 G244V | loss of function | |
| MLH1 G357A | unknown | |
| MLH1 G454R | no effect - predicted | |
| MLH1 G532C | unknown | |
| MLH1 G54E | loss of function | |
| MLH1 G65D | loss of function | |
| MLH1 G67R | loss of function | |
| MLH1 G67W | loss of function | |
| MLH1 H109D | unknown | |
| MLH1 H109P | loss of function - predicted | |
| MLH1 H109Q | no effect - predicted | |
| MLH1 H112D | unknown | |
| MLH1 H112Q | unknown | |
| MLH1 H264Lfs*2 | loss of function - predicted | |
| MLH1 H264Y | loss of function - predicted | |
| MLH1 H308P | loss of function - predicted | |
| MLH1 H315Y | unknown | |
| MLH1 H329P | unknown | |
| MLH1 H543R | unknown | |
| MLH1 H718Y | no effect | |
| MLH1 H733Qfs*14 | loss of function - predicted | |
| MLH1 hypermethylation | unknown | |
| MLH1 I107R | loss of function | |
| MLH1 I190T | unknown | |
| MLH1 I19F | loss of function - predicted | |
| MLH1 I219L | no effect | |
| MLH1 I219V | no effect | |
| MLH1 I25F | unknown | |
| MLH1 I25T | no effect - predicted | |
| MLH1 I262M | unknown | |
| MLH1 I276R | loss of function - predicted | |
| MLH1 I32V | unknown | |
| MLH1 I330del | loss of function | |
| MLH1 I501del | no effect - predicted | |
| MLH1 I565F | loss of function - predicted | |
| MLH1 I565M | unknown | |
| MLH1 I565T | unknown | |
| MLH1 I630S | unknown | |
| MLH1 I655T | no effect - predicted | |
| MLH1 I655V | no effect - predicted | |
| MLH1 I68N | loss of function - predicted | |
| MLH1 I68V | no effect - predicted | |
| MLH1 inact mut | loss of function | |
| MLH1 K118N | loss of function - predicted | |
| MLH1 K195* | loss of function | |
| MLH1 K241N | unknown | |
| MLH1 K254N | unknown | |
| MLH1 K286Q | no effect - predicted | |
| MLH1 K443Q | no effect | |
| MLH1 K618A | unknown | |
| MLH1 K618del | loss of function - predicted | |
| MLH1 K618E | unknown | |
| MLH1 K618R | unknown | |
| MLH1 K618T | unknown | |
| MLH1 K751R | no effect - predicted | |
| MLH1 K84E | loss of function | |
| MLH1 L135V | no effect - predicted | |
| MLH1 L155P | unknown | |
| MLH1 L155R | loss of function | |
| MLH1 L260F | loss of function - predicted | |
| MLH1 L272V | no effect - predicted | |
| MLH1 L507* | loss of function - predicted | |
| MLH1 L507F | no effect - predicted | |
| MLH1 L549P | loss of function | |
| MLH1 L550I | unknown | |
| MLH1 L550P | unknown | |
| MLH1 L555P | loss of function | |
| MLH1 L559R | loss of function | |
| MLH1 L574P | loss of function | |
| MLH1 L582F | loss of function - predicted | |
| MLH1 L582P | unknown | |
| MLH1 L582V | loss of function - predicted | |
| MLH1 L588P | loss of function | |
| MLH1 L588R | unknown | |
| MLH1 L590I | unknown | |
| MLH1 L607H | unknown | |
| MLH1 L622H | unknown | |
| MLH1 L622P | loss of function - predicted | |
| MLH1 L636P | loss of function - predicted | |
| MLH1 L653R | loss of function - predicted | |
| MLH1 L658I | unknown | |
| MLH1 L676P | loss of function - predicted | |
| MLH1 L676R | loss of function | |
| MLH1 L729V | no effect - predicted | |
| MLH1 L73P | loss of function | |
| MLH1 L749* | loss of function | |
| MLH1 L749P | loss of function | |
| MLH1 L85P | loss of function - predicted | |
| MLH1 LOH | unknown | |
| MLH1 loss | loss of function | |
| MLH1 M35R | loss of function - predicted | |
| MLH1 M383V | unknown | |
| MLH1 M524I | unknown | |
| MLH1 M587Hfs*6 | loss of function - predicted | |
| MLH1 M587V | unknown | |
| MLH1 mutant | unknown | |
| MLH1 N187Y | unknown | |
| MLH1 N215S | unknown | |
| MLH1 N338S | no effect - predicted | |
| MLH1 N38D | loss of function | |
| MLH1 N38H | loss of function - predicted | |
| MLH1 N38K | loss of function - predicted | |
| MLH1 N551S | unknown | |
| MLH1 N551T | unknown | |
| MLH1 N64S | unknown | |
| MLH1 negative | loss of function | PD-L1/PD-1 antibody Ipilimumab + Nivolumab |
| BRAF mut MLH1 neg | ||
| MLH1 P141A | no effect - predicted | |
| MLH1 P28L | loss of function | |
| MLH1 P403S | no effect - predicted | |
| MLH1 P496L | no effect - predicted | |
| MLH1 P578_E632del | loss of function | |
| MLH1 P581L | no effect - predicted | |
| MLH1 P603R | no effect - predicted | |
| MLH1 P640L | loss of function - predicted | |
| MLH1 P640S | loss of function - predicted | |
| MLH1 P640T | loss of function - predicted | |
| MLH1 P648L | unknown | |
| MLH1 P648S | unknown | |
| MLH1 P654L | loss of function | |
| MLH1 P709Q | unknown | |
| MLH1 positive | unknown | |
| MLH1 Q26R | unknown | |
| MLH1 Q391R | unknown | |
| MLH1 Q48E | unknown | |
| MLH1 Q48P | unknown | |
| MLH1 Q542L | loss of function | |
| MLH1 Q562P | unknown | |
| MLH1 Q60P | loss of function - predicted | |
| MLH1 Q689R | no effect | |
| MLH1 Q701K | unknown | |
| MLH1 R100* | loss of function - predicted | |
| MLH1 R100P | loss of function | |
| MLH1 R100Q | loss of function | |
| MLH1 R127K | loss of function - predicted | |
| MLH1 R182G | unknown | |
| MLH1 R217C | unknown | |
| MLH1 R226* | loss of function - predicted | |
| MLH1 R226L | loss of function - predicted | |
| MLH1 R226Q | unknown | |
| MLH1 R265C | loss of function | |
| MLH1 R265H | no effect | |
| MLH1 R265P | loss of function - predicted | |
| MLH1 R265S | loss of function | |
| MLH1 R325W | unknown | |
| MLH1 R385C | no effect - predicted | |
| MLH1 R389Q | no effect - predicted | |
| MLH1 R389W | unknown | |
| MLH1 R474G | no effect - predicted | |
| MLH1 R474P | no effect - predicted | |
| MLH1 R474Q | no effect | |
| MLH1 R474W | no effect - predicted | |
| MLH1 R487* | loss of function - predicted | |
| MLH1 R487L | unknown | |
| MLH1 R497Gfs*11 | loss of function - predicted | |
| MLH1 R498Efs*10 | loss of function - predicted | |
| MLH1 R498Efs*5 | loss of function - predicted | |
| MLH1 R522Gfs*13 | loss of function - predicted | |
| MLH1 R522W | unknown | |
| MLH1 R575G | unknown | |
| MLH1 R575K | no effect - predicted | |
| MLH1 R659* | loss of function - predicted | |
| MLH1 R659L | loss of function | |
| MLH1 R659P | loss of function | |
| MLH1 R659Q | no effect | |
| MLH1 R687W | unknown | |
| MLH1 R69K | no effect - predicted | |
| MLH1 R725C | unknown | |
| MLH1 R725H | unknown | |
| MLH1 R755S | unknown | |
| MLH1 R755W | loss of function - predicted | |
| MLH1 R9Q | unknown | |
| MLH1 R9W | unknown | |
| MLH1 S106R | loss of function - predicted | |
| MLH1 S193P | loss of function - predicted | |
| MLH1 S247P | loss of function | |
| MLH1 S252* | loss of function - predicted | |
| MLH1 S271F | unknown | |
| MLH1 S295G | unknown | |
| MLH1 S368L | unknown | |
| MLH1 S406N | no effect | |
| MLH1 S420C | no effect - predicted | |
| MLH1 S44F | loss of function | |
| MLH1 S46I | unknown | |
| MLH1 S505Vfs*3 | loss of function - predicted | |
| MLH1 S508N | unknown | |
| MLH1 S556N | unknown | |
| MLH1 S627T | no effect - predicted | |
| MLH1 S677Rfs*15 | loss of function - predicted | |
| MLH1 S685F | loss of function - predicted | |
| MLH1 S692P | unknown | |
| MLH1 S698L | unknown | |
| MLH1 S93G | no effect | |
| MLH1 T116K | unknown | |
| MLH1 T117M | loss of function | |
| MLH1 T117R | loss of function | |
| MLH1 T347I | unknown | |
| MLH1 T413I | no effect - predicted | |
| MLH1 T45_I47delinsCF | loss of function | |
| MLH1 T662P | unknown | |
| MLH1 T81I | unknown | |
| MLH1 T82A | loss of function | |
| MLH1 T82I | loss of function | |
| MLH1 V113D | loss of function - predicted | |
| MLH1 V16L | unknown | |
| MLH1 V179D | unknown | |
| MLH1 V180G | loss of function - predicted | |
| MLH1 V185G | loss of function | |
| MLH1 V194I | unknown | |
| MLH1 V213M | no effect | |
| MLH1 V326A | unknown | |
| MLH1 V384D | loss of function | |
| MLH1 V440M | unknown | |
| MLH1 V4A | unknown | |
| MLH1 V506A | unknown | |
| MLH1 V612del | loss of function - predicted | |
| MLH1 V716M | no effect | |
| MLH1 W666R | loss of function - predicted | |
| MLH1 W712* | loss of function - predicted | |
| MLH1 W714* | loss of function - predicted | |
| MLH1 Y126N | unknown | |
| MLH1 Y379C | unknown | |
| MLH1 Y646C | unknown | |
| MLH1 Y750* | loss of function - predicted | |
| MLH1 Y97D | loss of function - predicted |
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