ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.287G>A (p.Arg96His) (rs63750002)

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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) RCV000076555 SCV000107584 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000164188 SCV000214808 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification;Does not segregate with disease in family study (genes with incomplete penetrance)
Invitae RCV000524401 SCV000253157 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000442211 SCV000516099 likely benign not specified 2017-03-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000164188 SCV000685076 likely benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Counsyl RCV000662472 SCV000784966 likely benign Lynch syndrome I 2017-02-23 criteria provided, single submitter clinical testing
Mendelics RCV000662472 SCV001135697 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000442211 SCV001339206 likely benign not specified 2020-03-30 criteria provided, single submitter clinical testing Variant summary: MSH2 c.287G>A (p.Arg96His) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.287G>A has been reported in the literature together with an MSH2 frameshift variant in a family affected with Lynch Syndrome, authors noted that the variant of interest did not segregate with the disease (Wijnen_1995). In addition, a co-occurrence with a (likely) pathogenic variant has also been reported (RAD51C c.1026+5_1026+7delGTA; in an LCA internal sample), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no effect on MMR activity for this variant (Martinez_2010, Houlleberghs_2016). Six submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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