NM_000251.3(MSH2):c.943-1G>C AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Nov 28, 2017)

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.943-1G>C]


MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000002.12:g.47416295G>C
  • NG_007110.2:g.18172G>C
  • NM_000251.2:c.943-1G>C
  • NM_000251.3:c.943-1G>CMANE SELECT
  • NM_001258281.1:c.745-1G>C
  • LRG_218t1:c.943-1G>C
  • LRG_218:g.18172G>C
  • NC_000002.11:g.47643434G>C
  • NM_000251.1:c.943-1G>C
dbSNP: rs12476364
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.2:c.943-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000251.3:c.943-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258281.1:c.745-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]


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)
SCV000580427Ambry Geneticscriteria provided, single submitter
(Nov 28, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV000580427.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.943-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MSH2 gene. This variant was detected in several individuals meeting either Bethesda or Amsterdam II criteria for Lynch syndrome (Ambry internal data; Mangold E et al. Int. J. Cancer 2005;116(5):692-702). In addition, this alteration has been identified in individuals exhibiting high microsatellite instability (MSI-H) and/or loss of MSH2 expression on immunohistochemistry (IHC) in their colorectal tumors (Ambry internal data; Mangold E et al. J Pathol. 2005 Dec;207(4):385-95). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Another pathogenic variant at the same position, c.943-1G>T, was identified in several individuals exhibiting loss of MSH2 as well as MSH6 in their colorectal/endometrial tumors on IHC and had family histories that met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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

Last Updated: Oct 30, 2021

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