ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1759G>C (p.Gly587Arg) (rs63751140)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076270 SCV000107290 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (full inactivation of variant allele)
Invitae RCV000700587 SCV000829346 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 587 of the MSH2 protein (p.Gly587Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 11 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 observed in several individuals affected with Lynch syndrome-associated cancers (PMID: 21642682, 27601186, 20587412, 22067334). ClinVar contains an entry for this variant (Variation ID: 90771). Based on a multifactorial likelihood algorithm using clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change can result in skipping of exon 11 (PMID: 18561205). 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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