ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3478G>A (p.Val1160Ile) (rs376799914)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165060 SCV000215761 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001082754 SCV000254316 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000656900 SCV000279109 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3478G>A at the cDNA level, p.Val1160Ile (V1160I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has been observed in at least three individuals with personal and/or family history of breast and/or ovarian cancer (Maxwell 2015, Pinto 2016, Yadav 2016). MSH6 Val1160Ile was observed at an allele frequency of 0.12% (12/10,150) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val1160Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Val1160Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410385 SCV000487884 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656900 SCV000805892 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing
Mendelics RCV000708889 SCV000837916 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656900 SCV000888275 uncertain significance not provided 2019-01-22 criteria provided, single submitter clinical testing
Color RCV000165060 SCV000902810 likely benign Hereditary cancer-predisposing syndrome 2015-06-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000201982 SCV000919736 uncertain significance not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3478G>A (p.Val1160Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) found in proteins in the MutS family of DNA mismatch repair proteins. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui 2013). The variant allele was found at a frequency of 7.2e-05 in 251404 control chromosomes, predominantly at a frequency of 0.0012 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8 fold higher than the expected maximum for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant might be a benign polymorphism. c.3478G>A has been reported in the literature in individuals affected with Breast Cancer (Maxwell 2015, Pinto 2016, Yadav 2016), however, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2309C>A, p.Ser770X (Pinto 2016); BRCA2 c.5946delT, p.Ser1982ArgfsX22 (in an LCA internal sample)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as uncertain significance and onces as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Clinical Services Laboratory,Illumina RCV000410385 SCV001297512 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-09-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201982 SCV000257258 uncertain significance not specified no assertion criteria provided research

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