ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1847C>G (p.Ser616Cys) (rs772363120)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210205 SCV000266203 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000524121 SCV000283732 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 616 of the MSH6 protein (p.Ser616Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs772363120, ExAC 0.04%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 224580). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000410099 SCV000489415 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-10-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575424 SCV000662410 likely benign Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000575424 SCV000908382 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284178 SCV001469819 uncertain significance not provided 2020-06-25 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000410099 SCV001737487 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2021-05-06 criteria provided, single submitter clinical testing The MSH6 c.1847C>G (p.Ser616Cys) missense change has a maximum subpopulation frequency of 0.042% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48026969-C-G?dataset=gnomad_r2_1). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with a personal history of thyroid, prostate, and kidney cancers (PMID: 26845104). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.

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