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NM_000249.4(MLH1):c.2042C>T (p.Ala681Val) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 27, 2021
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 nonpolyposis colorectal neoplasms
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

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

(Invitae Variant Classification Sherloc (09022015))
(Jun 27, 2021)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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



Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer.

Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG.

Hum Mutat. 2008 Mar;29(3):367-74.

PubMed [citation]

Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome.

Froggatt NJ, Brassett C, Koch DJ, Evans DG, Hodgson SV, Ponder BA, Maher ER.

J Med Genet. 1996 Sep;33(9):726-30.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000827373.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)


For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala681 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18033691, 8880570, 10037723, 12810663). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This variant has been observed in individual(s) with suspected Lynch syndrome (PMID: 21615986, 24710284, Invitae). ClinVar contains an entry for this variant (Variation ID: 90011). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 681 of the MLH1 protein (p.Ala681Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine.

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

Last Updated: Jun 9, 2024