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NM_000249.4(MLH1):c.2042C>T (p.Ala681Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 17, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.2042C>T (p.Ala681Val)]

NM_000249.4(MLH1):c.2042C>T (p.Ala681Val)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.2042C>T (p.Ala681Val)
  • NC_000003.12:g.37048956C>T
  • NG_007109.2:g.60607C>T
  • NM_000249.4:c.2042C>TMANE SELECT
  • NM_001167617.3:c.1748C>T
  • NM_001167618.3:c.1319C>T
  • NM_001167619.3:c.1319C>T
  • NM_001258271.2:c.1896+1273C>T
  • NM_001258273.2:c.1319C>T
  • NM_001258274.3:c.1319C>T
  • NM_001354615.2:c.1319C>T
  • NM_001354616.2:c.1319C>T
  • NM_001354617.2:c.1319C>T
  • NM_001354618.2:c.1319C>T
  • NM_001354619.2:c.1319C>T
  • NM_001354620.2:c.1748C>T
  • NM_001354621.2:c.1019C>T
  • NM_001354622.2:c.1019C>T
  • NM_001354623.2:c.1019C>T
  • NM_001354624.2:c.968C>T
  • NM_001354625.2:c.968C>T
  • NM_001354626.2:c.968C>T
  • NM_001354627.2:c.968C>T
  • NM_001354628.2:c.1949C>T
  • NM_001354629.2:c.1943C>T
  • NM_001354630.2:c.1877C>T
  • NP_000240.1:p.Ala681Val
  • NP_000240.1:p.Ala681Val
  • NP_001161089.1:p.Ala583Val
  • NP_001161090.1:p.Ala440Val
  • NP_001161091.1:p.Ala440Val
  • NP_001245202.1:p.Ala440Val
  • NP_001245203.1:p.Ala440Val
  • NP_001341544.1:p.Ala440Val
  • NP_001341545.1:p.Ala440Val
  • NP_001341546.1:p.Ala440Val
  • NP_001341547.1:p.Ala440Val
  • NP_001341548.1:p.Ala440Val
  • NP_001341549.1:p.Ala583Val
  • NP_001341550.1:p.Ala340Val
  • NP_001341551.1:p.Ala340Val
  • NP_001341552.1:p.Ala340Val
  • NP_001341553.1:p.Ala323Val
  • NP_001341554.1:p.Ala323Val
  • NP_001341555.1:p.Ala323Val
  • NP_001341556.1:p.Ala323Val
  • NP_001341557.1:p.Ala650Val
  • NP_001341558.1:p.Ala648Val
  • NP_001341559.1:p.Ala626Val
  • LRG_216t1:c.2042C>T
  • LRG_216:g.60607C>T
  • LRG_216p1:p.Ala681Val
  • NC_000003.11:g.37090447C>T
  • NM_000249.3:c.2042C>T
  • NM_001167618.1:c.1319C>T
Protein change:
dbSNP: rs63750864
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001258271.2:c.1896+1273C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.2042C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1748C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1748C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1019C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1019C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1019C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.968C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.968C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.968C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.968C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1943C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1877C>T - missense variant - [Sequence Ontology: SO:0001583]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV002719809Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Oct 17, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Distinct mutations in MLH1 and MSH2 genes in hereditary non-polyposis colorectal cancer (HNPCC) families from China.

Wei W, Liu F, Liu L, Li Z, Zhang X, Jiang F, Shi Q, Zhou X, Sheng W, Cai S, Li X, Xu Y, Nan P.

BMB Rep. 2011 May;44(5):317-22. doi: 10.5483/BMBRep.2011.44.5.317.

PubMed [citation]

Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.

Zhu M, Chen HM, Wang YP.

Oncol Lett. 2013 May;5(5):1710-1718. Epub 2013 Mar 11.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002719809.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


The p.A681V variant (also known as c.2042C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2042. The alanine at codon 681 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple families meeting Amsterdam or Bethesda criteria (Wei W et al. BMB Rep. 2011 May; 44(5):317-22; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). This alteration has also been identified as either somatic or in the germline of individuals whose colorectal tumors demonstrated loss of both MLH1 and PMS2 on immunohistochemistry and/or high microsatellite instability (Herfarth KK et al. Genes Chromosomes Cancer. 1997 Jan;18:42-9; Geurts-Giele WR et al. J. Pathol. 2014 Dec;234:548-59); Liu Y et al. PLoS ONE. 2014 Apr;9:e94170; Ambry internal data). Further, a well-characterized mutation at the same codon, p.A681T (c.2041G>A), has been identified in multiple families either meeting Amsterdam II criteria or whose family history was suggestive of HNPCC/Lynch syndrome and has also been shown to co-segregate with disease (Froggatt et al. J Med Genet. 1996 Sep; 33(9): 762-30; Shimodaira et al. Nat Genet 1998 Aug; 19(4): 384-9; Kurzawski G et al. Clin. Genet. 2006 Jan; 69(1):40-7; Barnetson RA et al. Hum. Mutat. 2008 Mar; 29(3):367-74). Based on an internal structural assessment, the p.A681V alteration locally destabilizes the folding of the MLH1 C-terminal domain (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 9, 2024