ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.905G>C (p.Arg302Thr) (rs587781510)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129487 SCV000184258 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761043 SCV000890958 uncertain significance Medulloblastoma, desmoplastic 2016-04-27 no assertion criteria provided clinical testing
Color RCV000129487 SCV000685529 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000662957 SCV000785927 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000589579 SCV000279833 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.905G>C at the cDNA level, p.Arg302Thr (R302T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Arg302Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signal (Gassman 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 Arg302Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589579 SCV000695934 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.905G>C (p.Arg302Thr) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 7/121162 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0005191 (6/11558). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. Multiple clinical diagnostic laboratories have classified this variant as VUS, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the c.905G>C has been classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Invitae RCV000168210 SCV000218875 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 302 of the MSH6 protein (p.Arg302Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs587781510, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141122). 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.
Mendelics RCV000708859 SCV000837873 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216085 SCV000601621 uncertain significance not specified 2016-11-09 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000129487 SCV000788059 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 no assertion criteria provided clinical testing

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