NM_000251.2(MSH2):c.1276+1G>A AND Hereditary nonpolyposis colorectal neoplasms

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

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_000251.2(MSH2):c.1276+1G>A]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47429942G>A
  • NG_007110.2:g.31819G>A
  • NM_000251.2:c.1276+1G>A
  • NM_000251.3:c.1276+1G>AMANE SELECT
  • NM_001258281.1:c.1078+1G>A
  • LRG_218t1:c.1276+1G>A
  • LRG_218:g.31819G>A
  • NC_000002.11:g.47657081G>A
  • NM_000251.1:c.1276+1G>A
dbSNP: rs267607950
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.2:c.1276+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258281.1:c.1078+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)


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)
SCV000625246Invitaecriteria provided, single submitter
(Aug 26, 2020)
germlineclinical testing

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

Summary from all submissions

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



Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000625246.4

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


This sequence change affects a donor splice site in intron 7 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (rs267607950, ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome (PMID: 15849733, 19669161, 21520333). ClinVar contains an entry for this variant (Variation ID: 90590). Experimental studies have shown that this splice donor change causes the activation of a cryptic splice site in exon 7 resulting in the in-frame deletion of 16 amino acids in vitro (PMID: 19669161). Deletion of this region is expected to disrupt the MSH3/MSH6 interaction domain, which is required for proper MSH2 protein function (PMID: 18822302, 9774676). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2021

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