ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.831A>C (p.Glu277Asp) (rs374486449)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235181 SCV000211263 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.831A>C at the cDNA level, p.Glu277Asp (E277D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant has been reported in at least one individual with breast cancer (Tung 2015). MSH6 Glu277Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Glu277Asp is located within a nuclear localization signal (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 Glu277Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160656 SCV000217992 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000196039 SCV000254334 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 277 of the MSH6 protein (p.Glu277Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs374486449, ExAC 0.04%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 182612). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. The aspartic acid 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.
Counsyl RCV000411901 SCV000488512 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-04-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781597 SCV000919768 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.831A>C (p.Glu277Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant and a study combining data from several in silico tools and structural analyses predicts the variant to have no effect on MSH6 function (Terui_2013). The variant allele was found at a frequency of 2.5e-05 (7/276832 control chromosomes) in all ethnicities, but was found predominantly in the African subpopulation (6/24016; frequency of 0.00025). This frequency is approximately 2 fold higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (0.00025vs 0.00014), suggesting the variant may be a benign polymorphism in the African subpopulation. To our knowledge, no occurrence of c.831A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until addtional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235181 SCV001134457 uncertain significance not provided 2018-11-25 criteria provided, single submitter clinical testing
Color RCV000160656 SCV001356388 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-11 criteria provided, single submitter clinical testing

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