NM_000251.3(MSH2):c.942+2T>A AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Oct 6, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001229248.2

Allele description [Variation Report for NM_000251.3(MSH2):c.942+2T>A]

NM_000251.3(MSH2):c.942+2T>A

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.942+2T>A
HGVS:
  • NC_000002.12:g.47414420T>A
  • NG_007110.2:g.16297T>A
  • NM_000251.2:c.942+2T>A
  • NM_000251.3:c.942+2T>AMANE SELECT
  • NM_001258281.1:c.744+2T>A
  • LRG_218t1:c.942+2T>A
  • LRG_218:g.16297T>A
  • NC_000002.11:g.47641559T>A
  • NM_000251.1:c.942+2T>A
Links:
dbSNP: rs587779195
NCBI 1000 Genomes Browser:
rs587779195
Molecular consequence:
  • NM_000251.2:c.942+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000251.3:c.942+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258281.1:c.744+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001401688Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 6, 2020)
germlineclinical testing

PubMed (6)
[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

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]
PMID:
25980754
PMCID:
PMC4550537

Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.

De Lellis L, Aceto GM, Curia MC, Catalano T, Mammarella S, Veschi S, Fantini F, Battista P, Stigliano V, Messerini L, Mareni C, Sala P, Bertario L, Radice P, Cama A.

PLoS One. 2013;8(11):e81194. doi: 10.1371/journal.pone.0081194.

PubMed [citation]
PMID:
24278394
PMCID:
PMC3835792
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001401688.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in intron 5 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 individuals affected with Lynch syndrome (PMID: 25980754, 24278394). ClinVar contains an entry for this variant (Variation ID: 428474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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