NM_000251.3(MSH2):c.1276+7A>G AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Mar 21, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.1276+7A>G]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47429948A>G
  • NG_007110.2:g.31825A>G
  • NM_000251.3:c.1276+7A>GMANE SELECT
  • NM_001258281.1:c.1078+7A>G
  • LRG_218t1:c.1276+7A>G
  • LRG_218:g.31825A>G
  • NC_000002.11:g.47657087A>G
  • NM_000251.1:c.1276+7A>G
  • NM_000251.2:c.1276+7A>G
dbSNP: rs748554540
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.3:c.1276+7A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258281.1:c.1078+7A>G - intron variant - [Sequence Ontology: SO:0001627]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000713977GeneDxcriteria provided, single submitter
Likely benign
(Jul 3, 2017)
germlineclinical testing

Citation Link,

SCV000917694Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 21, 2018)
germlineclinical testing

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

Citation Link

Summary from all submissions

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



Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome.

Barrow E, Jagger E, Brierley J, Wallace A, Evans G, Hill J, McMahon R.

Histopathology. 2010 Feb;56(3):331-44. doi: 10.1111/j.1365-2559.2010.03485.x.

PubMed [citation]

Details of each submission

From GeneDx, SCV000713977.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917694.1

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


Variant summary: MSH2 c.1276+7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site, while one predicts the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 245846 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (1.2e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.1276+7A>G, has been reported in the literature in one individual affected with Lynch Syndrome without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) classifies the variant as "likely benign." Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 27, 2021

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