ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.211G>C (p.Gly71Arg) (rs587782659)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132075 SCV000187139 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503476 SCV000592455 likely pathogenic Lynch syndrome 2012-03-18 criteria provided, single submitter clinical testing
Invitae RCV000535324 SCV000625353 likely pathogenic Hereditary nonpolyposis colon cancer 2018-02-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 71 of the MSH2 protein (p.Gly71Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. It also falls at the last nucleotide of exon 1 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 28577310) and has been observed to segregate with Lynch syndrome-associated tumors in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 142708). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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