ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1746T>G (p.Phe582Leu) (rs201518545)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115382 SCV000216925 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115382 SCV000903501 likely benign Hereditary cancer-predisposing syndrome 2016-09-20 criteria provided, single submitter clinical testing
Counsyl RCV000409045 SCV000487946 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000235184 SCV000149291 uncertain significance not provided 2018-12-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1746T>G at the cDNA level, p.Phe582Leu (F582L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe582Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Phe582Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230963 SCV000283726 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 582 of the MSH6 protein (p.Phe582Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs201518545, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127563). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. In addition, the leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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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