ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1037C>T (p.Ser346Phe) (rs567785169)

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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 RCV000167468 SCV000218324 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000167468 SCV000911012 likely benign Hereditary cancer-predisposing syndrome 2016-03-16 criteria provided, single submitter clinical testing
Counsyl RCV000662908 SCV000785833 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000657019 SCV000566406 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1037C>T at the cDNA level, p.Ser346Phe (S346F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser346Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signals (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 Ser346Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000229553 SCV000430956 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000524097 SCV000283694 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 346 of the MSH6 protein (p.Ser346Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs567785169, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 187718). 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 phenylalanine 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454816 SCV000539716 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ser346Phe variant in MSH6 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 1/66640 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs567785169). Serine (Ser) at position 346 is not conserved in mammals or evolutionarily distant species and 36 species (including 3 mammals) carry a Phenylalanine (Phe), raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that the p.Ser346Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ser346Phe variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000454816 SCV000601499 uncertain significance not specified 2017-06-29 criteria provided, single submitter clinical testing

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