ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4001G>C (p.Arg1334Pro) (rs267608122)

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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 RCV000219938 SCV000277547 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-12 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Last nucleotide of exon
Invitae RCV000459481 SCV000551274 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1334 of the MSH6 protein (p.Arg1334Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant also falls at the last nucleotide of exon 9 of the MSH6 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 MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 233214). 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. This variant disrupts the c.4001G nucleotide in the MSH6 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10508506, 17453009, 21836479, 18415027). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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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