ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1844G>T (p.Cys615Phe) (rs730881793)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165560 SCV000216293 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168072 SCV000218726 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 615 of the MSH6 protein (p.Cys615Phe). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 186038). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000479956 SCV000565218 uncertain significance not provided 2018-12-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1844G>T at the cDNA level, p.Cys615Phe (C615F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). This variant has been observed in at least two individuals with colorectal cancer as well as in a cohort of patients with advanced cancer (Mandelker 2017, Yurgelun 2017). MSH6 Cys615Phe was observed at an allele frequency of 0.02% (2/8,730) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (Warren 2007, Kasikas 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 Cys615Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165560 SCV000690226 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing

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