NM_000251.3(MSH2):c.1276+1G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 4, 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.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_000251.3: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
  • NM_000251.2:c.1276+1G>A
dbSNP: rs267607950
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000251.3: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 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)
SCV000580472Ambry Geneticscriteria provided, single submitter
(May 4, 2020)
germlineclinical testing

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

Citation Link,

SCV000684922Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Apr 3, 2019)
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



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]

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]
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000580472.4

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


The c.1276+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the MSH2 gene. This mutation has been identified in multiple Lynch syndrome families to date and shown to cause aberrant splicing by RNA analyses (Mangold E et al, Int. J. Cancer 2005 Sep; 116(5):692-702; Betz B et al, J. Cancer Res. Clin. Oncol. 2010 Jan; 136(1):123-34). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). 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

From Color Health, Inc, SCV000684922.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 2, 2021

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