NM_000251.3(MSH2):c.366+1G>A AND Hereditary nonpolyposis colon cancer

Clinical significance:Pathogenic (Last evaluated: Jun 1, 2021)

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.366+1G>A]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47408556G>A
  • NG_007110.2:g.10433G>A
  • NM_000251.3:c.366+1G>AMANE SELECT
  • NM_001258281.1:c.168+1G>A
  • LRG_218t1:c.366+1G>A
  • LRG_218:g.10433G>A
  • NC_000002.11:g.47635695G>A
  • NM_000251.1:c.366+1G>A
  • NM_000251.2:c.366+1G>A
dbSNP: rs267607924
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.3:c.366+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258281.1:c.168+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]


Hereditary nonpolyposis colon cancer (HNPCC)
Hereditary nonpolyposis colorectal cancer
MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000696262Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
(Jun 1, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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



Genetic features of Lynch syndrome in the Israeli population.

Goldberg Y, Barnes-Kedar I, Lerer I, Halpern N, Plesser M, Hubert A, Kadouri L, Goldshmidt H, Solar I, Strul H, Rosner G, Baris HN, Peretz T, Levi Z, Kariv R.

Clin Genet. 2015 Jun;87(6):549-53. doi: 10.1111/cge.12530. Epub 2014 Nov 28.

PubMed [citation]

Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.

Haraldsdottir S, Hampel H, Tomsic J, Frankel WL, Pearlman R, de la Chapelle A, Pritchard CC.

Gastroenterology. 2014 Dec;147(6):1308-1316.e1. doi: 10.1053/j.gastro.2014.08.041. Epub 2014 Sep 3.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696262.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


Variant summary: MSH2 c.366+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250038 control chromosomes. c.366+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome (Geary_2008, Goldberg_2014, Sjursen_2016). The variant has also been reported as a somatic occurrence in the MMR deficient tumor of a 71-year old female who was indicated to harbor another potentially pathogenic MSH2 variant, c.1738G>T (p.Glu580X) presumably due to LOH (Haraldsdottir_2014). This individual had previously tested negative for MMR germline mutations by Sanger sequencing, MLPA, and MLH1 hypermethylation and did not fulfill the Amsterdam-II or the revised Bethesda criteria for Lynch syndrome. These data indicate that the variant is very likely to be associated with disease in both germline and somatic settings. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 27, 2021

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