ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1028C>T (p.Pro343Leu) (rs548898238)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212641 SCV000149275 uncertain significance not provided 2018-12-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1028C>T at the cDNA level, p.Pro343Leu (P343L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Pro343Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signals (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Pro343Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115366 SCV000186100 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000469621 SCV000551201 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 343 of the MSH6 protein (p.Pro343Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs548898238, ExAC 0.01%). This variant has been reported in individuals referred for hereditary cancer panel testing (PMID: 25318351). ClinVar contains an entry for this variant (Variation ID: 127552). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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