ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206061 SCV000261641 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-03 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 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217423 SCV000601523 uncertain significance not specified 2017-01-26 criteria provided, single submitter clinical testing
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 2018-05-22 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 RCV000491346 SCV000911025 likely benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000217423 SCV000919746 uncertain significance not specified 2018-03-30 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. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.00013 (4/30768 control chromosomes)(gnomAD). This frequency is similar to the maximal expected frequency for a pathogenic variant in MSH6 causing Lynch Syndrome (0.00013 vs 0.00014). Additionally, all 4 variant alleles in gnomAD were found within the African subpopulation for a frequency of 0.00046, which is approximately 3 times above the maximal expected pathogenic frequency, suggesting the variant may be benign. However, with so few variant alleles and data from only ~15,000 individuals in gnomAD, additional data is necessary to accurately assess the true frequency of the variant in the general population. To our knowledge, no occurrence of c.187T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. An internal sample reports the variant to co-occur with a pathogenic CHEK2 c.1100delC mutation, suggesting the variant of interest may not be the cause of disease in this individual. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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