ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.187T>C (p.Ser63Pro) (rs763702846)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206061 SCV000261641 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 63 of the MSH6 protein (p.Ser63Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 220796). 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.
GeneDx RCV000656886 SCV000279091 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.187T>C at the cDNA level, p.Ser63Pro (S63P) at the protein level, and results in the change of a Serine to a Proline (TCC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser63Pro was observed at an allele frequency of 0.05% (4/8,676) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ser63Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491346 SCV000580254 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing The p.S63P variant (also known as c.187T>C), located in coding exon 1 of the MSH6 gene, results from a T to C substitution at nucleotide position 187. The serine at codon 63 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000663184 SCV000786355 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-04-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656886 SCV000889464 uncertain significance not provided 2019-08-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765679 SCV000897021 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491346 SCV000911025 likely benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217423 SCV000919746 uncertain significance not specified 2021-02-05 criteria provided, single submitter clinical testing Variant summary: MSH6 c.187T>C (p.Ser63Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 145552 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Co-occurrence with a pathogenic variant has been reported (CHEK2 c.1100delC, p.Thr367MetfsX15), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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