ClinVar Miner

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

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Total submissions: 4
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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.
Integrated Genetics/Laboratory Corporation of America RCV000471120 SCV000696262 pathogenic Lynch syndrome 2018-11-26 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 245016 control chromosomes (gnomAD). 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000791394 SCV000548172 pathogenic Hereditary nonpolyposis colon cancer 2018-10-29 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.
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.

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