ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.650A>G (p.Asp217Gly) (rs554012110)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131354 SCV000186329 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212632 SCV000211258 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.650A>G at the cDNA level, p.Asp217Gly (D217G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was observed in at least one individual with ovarian cancer (Pal 2012). MSH6 Asp217Gly was observed at an allele frequency of 0.034% (8/23898) in individuals of African ancestry in large population cohorts (Lek 2016). Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Asp217Gly is located within the nuclear localization signals (Gassman 2011). Although protein-based in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function, multiple splicing models predict the creation of a cryptic splice donor site, possibly leading to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH6 Asp217Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167904 SCV000218552 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 217 of the MSH6 protein (p.Asp217Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs554012110, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ovarian cancer and colorectal cancer (PMID: 23047549, 28944238). ClinVar contains an entry for this variant (Variation ID: 142305). 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 glycine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional 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 RCV000411184 SCV000489127 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-22 criteria provided, single submitter clinical testing
Color RCV000131354 SCV000685512 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing
Mendelics RCV000708856 SCV000837869 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212632 SCV001134454 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing

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