ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.491A>C (p.His164Pro) (rs146469162)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131540 SCV000186538 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000656888 SCV000211257 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.491A>C at the cDNA level, p.His164Pro (H164P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has been reported in at least one individual with a personal history of breast cancer and family history of breast and/or ovarian cancer (Tung 2015). MSH6 His164Pro was observed at an allele frequency of 0.12% (29/24,028) 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 His164Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000656888 SCV000283845 likely benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212631 SCV000601608 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000662620 SCV000785283 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-06-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656888 SCV000888291 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing
Color RCV000131540 SCV000903020 likely benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212631 SCV000917751 likely benign not specified 2017-12-22 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.491A>C (p.His164Pro) variant located in the PWWP domain (via InterPro) involves the alteration of a conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in 31/277164 control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.001207 (29/24028). This frequency is about 8 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 African origin. In addition, an internal LCA specimen finds the variant to co-occur with a pathogenic MSH2 variant, c.942+3A>T (scored DV). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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. Taken together, this variant is classified as a "Likely Benign," until additional information becomes available.

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