ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1076G>A (p.Arg359Lys) (rs63751604)

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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 RCV000575936 SCV000669777 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000629803 SCV000750759 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 359 of the MSH2 protein (p.Arg359Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 6 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs63751604, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. 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. 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. A different missense substitution at this codon (p.Arg359Ser) has been determined to be pathogenic (PMID: 17250665, 17720936, 18781619, 24362816). This suggests that the arginine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be damaging. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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