ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1276+1G>A (rs267607950)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076086 SCV000107101 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000491508 SCV000580472 pathogenic Hereditary cancer-predisposing syndrome 2020-05-04 criteria provided, single submitter clinical testing 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 []). 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.
Invitae RCV000548164 SCV000625246 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (rs267607950, ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome (PMID: 15849733, 19669161, 21520333). ClinVar contains an entry for this variant (Variation ID: 90590). Experimental studies have shown that this splice donor change causes the activation of a cryptic splice site in exon 7 resulting in the in-frame deletion of 16 amino acids in vitro (PMID: 19669161). Deletion of this region is expected to disrupt the MSH3/MSH6 interaction domain, which is required for proper MSH2 protein function (PMID: 18822302, 9774676). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000491508 SCV000684922 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000786795 SCV001249232 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353592 SCV000592495 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The c.1276+1G>A variant was identified in 2 of 908 proband chromosomes (frequency: 0.02) from individuals or families with Lynch syndrome (Mangold 2005). The variant was also identified in dbSNP (ID: rs267607950) “With pathogenic, probable-pathogenic allele”, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the “MMR Gene Unclassified Variants Database”. The c.1276+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in all five programs. In a functional study, RT-PCR analysis of the variant allele found that the variant activated a cryptic 5’ splice site in exon 7, resulting in a deletion of 48 nucleotides from this exon, and ultimately an in-frame deletion of 16 amino acids of the hMSH3/hMSH6 interaction domain of the MSH2 protein (Betz 2010). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000786795 SCV000925685 not provided not provided no assertion provided in vitro
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001250019 SCV001423944 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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