NM_000251.3(MSH2):c.274C>G (p.Leu92Val) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Aug 26, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.274C>G (p.Leu92Val)]

NM_000251.3(MSH2):c.274C>G (p.Leu92Val)

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.274C>G (p.Leu92Val)
  • NC_000002.12:g.47408463C>G
  • NG_007110.2:g.10340C>G
  • NM_000251.3:c.274C>GMANE SELECT
  • NM_001258281.1:c.76C>G
  • NP_000242.1:p.Leu92Val
  • NP_000242.1:p.Leu92Val
  • NP_001245210.1:p.Leu26Val
  • LRG_218t1:c.274C>G
  • LRG_218:g.10340C>G
  • LRG_218p1:p.Leu92Val
  • NC_000002.11:g.47635602C>G
  • NM_000251.1:c.274C>G
  • NM_000251.2:c.274C>G
Protein change:
dbSNP: rs587779154
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.3:c.274C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.76C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
Unknown function


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000277387Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Mar 31, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000690095Color Health, Inccriteria provided, single submitter
Uncertain significance
(Aug 26, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Comparative in silico analyses and experimental validation of novel splice site and missense mutations in the genes MLH1 and MSH2.

Betz B, Theiss S, Aktas M, Konermann C, Goecke TO, Möslein G, Schaal H, Royer-Pokora B.

J Cancer Res Clin Oncol. 2010 Jan;136(1):123-34. doi: 10.1007/s00432-009-0643-z.

PubMed [citation]

Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6.

Taeubner J, Wimmer K, Muleris M, Lascols O, Colas C, Fauth C, Brozou T, Felsberg J, Riemer J, Gombert M, Ginzel S, Hoell JI, Borkhardt A, Kuhlen M.

Eur J Hum Genet. 2018 Mar;26(3):440-444. doi: 10.1038/s41431-017-0071-5. Epub 2018 Jan 4.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000277387.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)


The p.L92V variant (also known as c.274C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide position 274. The leucine at codon 92 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000690095.4

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


This missense variant replaces leucine with valine at codon 92 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. The primary cause of the disease is not clear. This variant has been identified in 15/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Dec 4, 2021

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