NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Nov 29, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)]

NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)
  • NC_000002.12:g.47476436G>A
  • NG_007110.2:g.78313G>A
  • NM_000251.2:c.2075G>A
  • NM_000251.3:c.2075G>AMANE SELECT
  • NM_001258281.1:c.1877G>A
  • NP_000242.1:p.Gly692Glu
  • NP_000242.1:p.Gly692Glu
  • NP_001245210.1:p.Gly626Glu
  • LRG_218t1:c.2075G>A
  • LRG_218:g.78313G>A
  • LRG_218p1:p.Gly692Glu
  • NC_000002.11:g.47703575G>A
  • NC_000002.11:g.47703575G>A
Protein change:
dbSNP: rs63751432
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.2:c.2075G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000251.3:c.2075G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1877G>A - missense variant - [Sequence Ontology: SO:0001583]


Hereditary nonpolyposis colorectal neoplasms
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000943704Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 29, 2019)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

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



UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.

Béroud C, Collod-Béroud G, Boileau C, Soussi T, Junien C.

Hum Mutat. 2000;15(1):86-94.

PubMed [citation]

Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination.

Studamire B, Price G, Sugawara N, Haber JE, Alani E.

Mol Cell Biol. 1999 Nov;19(11):7558-67.

PubMed [citation]
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000943704.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)


This sequence change replaces glycine with glutamic acid at codon 692 of the MSH2 protein (p.Gly692Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). Also, this variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 265620). 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 MSH2 protein function. Variants that disrupt the p.Gly692 amino acid residue in MSH2 have been observed in individuals affected with Lynch syndrome and constitutional mismatch repair deficiency (PMID: 10523644, 28577310, 15713769, 10612836, 29212164, 28135145, 23454724). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 25, 2021

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