ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.366+1G>A (rs267607924)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236788 SCV000293166 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.366+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the MSH2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. While splicing based functional assays have not been completed for this specific variant, a similar variant involving the same nucleotide, MSH2 c.366+1G>T, has been reportedly confirmed to result in skipping of exon 2 via RT-PCR (Auclair 2006). This variant has been reported in at least two individuals with Lynch syndrome (Geary 2008, Sjursen 2016). Based on current evidence, we consider MSH2 c.366+1G>A to be pathogenic.
Invitae RCV000791394 SCV000548172 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 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 with clinical features of Lynch syndrome (PMID: 17939062, 27064304, 25430799). Additionally, it has also been observed to segregate with disease in Lynch syndrome families (Invitae). ClinVar contains an entry for this variant (Variation ID: 245947). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526857 SCV000696262 pathogenic Hereditary nonpolyposis colon cancer 2021-06-01 criteria provided, single submitter clinical testing Variant summary: MSH2 c.366+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250038 control chromosomes. c.366+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome (Geary_2008, Goldberg_2014, Sjursen_2016). The variant has also been reported as a somatic occurrence in the MMR deficient tumor of a 71-year old female who was indicated to harbor another potentially pathogenic MSH2 variant, c.1738G>T (p.Glu580X) presumably due to LOH (Haraldsdottir_2014). This individual had previously tested negative for MMR germline mutations by Sanger sequencing, MLPA, and MLH1 hypermethylation and did not fulfill the Amsterdam-II or the revised Bethesda criteria for Lynch syndrome. These data indicate that the variant is very likely to be associated with disease in both germline and somatic settings. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000471120 SCV000887346 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.366+1G>A has a 99.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics RCV001020825 SCV001182356 pathogenic Hereditary cancer-predisposing syndrome 2020-09-18 criteria provided, single submitter clinical testing 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.
Color Health, Inc RCV001020825 SCV001354851 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-01 criteria provided, single submitter clinical testing 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 ( Based on the available evidence, this variant is classified as Likely Pathogenic.

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