NM_000251.3(MSH2):c.366+1G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 18, 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.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 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)
SCV001182356Ambry Geneticscriteria provided, single submitter
(Sep 18, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001354851Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Jun 1, 2020)
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



Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC).

Geary J, Sasieni P, Houlston R, Izatt L, Eeles R, Payne SJ, Fisher S, Hodgson SV.

Fam Cancer. 2008;7(2):163-72. Epub 2007 Oct 16.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV001182356.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)


The c.366+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MSH2 gene. This alteration has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families to date (Geary J et al. Fam. Cancer. 2008 Oct;7:163-72; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53; Sjursen W et al. Mol. Genet. Genomic Med. 2016 Mar;4:223-31). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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, SCV001354851.2

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


This variant causes a G to A nucleotide substitution at the +1 position of intron 2 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 17939062, 27064304, 25430799). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: Nov 27, 2021

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