NM_000251.3(MSH2):c.646-2A>G AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Oct 30, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000817666.3

Allele description [Variation Report for NM_000251.3(MSH2):c.646-2A>G]

NM_000251.3(MSH2):c.646-2A>G

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.646-2A>G
HGVS:
  • NC_000002.12:g.47412412A>G
  • NG_007110.2:g.14289A>G
  • NM_000251.3:c.646-2A>GMANE SELECT
  • NM_001258281.1:c.448-2A>G
  • LRG_218t1:c.646-2A>G
  • LRG_218:g.14289A>G
  • NC_000002.11:g.47639551A>G
  • NM_000251.1:c.646-2A>G
  • NM_000251.2:c.646-2A>G
Links:
dbSNP: rs587779169
NCBI 1000 Genomes Browser:
rs587779169
Molecular consequence:
  • NM_000251.3:c.646-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258281.1:c.448-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000958243Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 30, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

Jóri B, Kamps R, Xanthoulea S, Delvoux B, Blok MJ, Van de Vijver KK, de Koning B, Oei FT, Tops CM, Speel EJ, Kruitwagen RF, Gomez-Garcia EB, Romano A.

Oncotarget. 2015 Dec 1;6(38):41108-22. doi: 10.18632/oncotarget.5694.

PubMed [citation]
PMID:
26517685
PMCID:
PMC4747393

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]
PMID:
12624141
PMCID:
PMC1735402
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000958243.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change affects an acceptor splice site in intron 3 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with endometrial cancer (PMID: 26517685), and several individuals affected with Lynch syndrome (PMID: 12624141, 21642682). This variant is also known as IVS3-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 91161). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Nov 27, 2021

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