ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3478G>A (p.Val1160Ile) (rs376799914)

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Total submissions: 10
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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 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165060 SCV000902810 likely benign Hereditary cancer-predisposing syndrome 2015-06-09 criteria provided, single submitter clinical testing
Counsyl RCV000410385 SCV000487884 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-25 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.
Integrated Genetics/Laboratory Corporation of America RCV000201982 SCV000919736 uncertain significance not specified 2018-03-05 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, found 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). However, these predictions have not been functionally studied. The variant, c.3478G>A, was observed with an allele frequency of 6.9e-05 in 277134 control chromosomes (gnomAD). The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, 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. In addition, in one of these publications (Pinto 2016), the variant was found in co-occurrence with another pathogenic variant (BRCA1 c.2309C>A, p.Ser770X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissisions from clinical diagnostic laboratories (evaluations after 2014) cite variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Invitae RCV000200058 SCV000254316 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1160 of the MSH6 protein (p.Val1160Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs376799914, ExAC 0.007%). This variant has been reported in individuals with personal or family history of breast and/or ovarian cancer (PMID: 25503501, 27878467, 27553368). ClinVar contains an entry for this variant (Variation ID: 185611). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. The isoleucine amino acid residue is also 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. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201982 SCV000257258 uncertain significance not specified no assertion criteria provided research
Mendelics RCV000708889 SCV000837916 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000656900 SCV000805892 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656900 SCV000888275 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing

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