ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1759G>A (p.Gly587Ser) (rs63751140)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568488 SCV000669833 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Last nucleotide of exon;Well-characterized mutation at same position;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000823865 SCV000964736 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 587 of the MSH2 protein (p.Gly587Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 483724). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant affecting this nucleotide (c.1759G>C) has been determined to be pathogenic (PMID: 21642682, 27601186, 20587412, 22067334,18561205). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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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