ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.743G>C (p.Arg248Pro) (rs764870249)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476123 SCV000551256 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 248 of the MSH6 protein (p.Arg248Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs764870249, 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: 410512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000587170 SCV000568152 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.743G>C at the cDNA level, p.Arg248Pro (R248P) at the protein level, and results in the change of an Arginine to a Proline (CGA>CCA). This variant has been reported in at least one individual with a Lynch syndrome-related cancer and/or colon polyps (Yurgelun 2015). MSH6 Arg248Pro was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg248Pro is located in the nuclear localization signal (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg248Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562563 SCV000662396 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000587170 SCV000695927 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.743G>C (p.Arg248Pro) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120946 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was found in an individual undergoing genetic testing for Lynch syndrome; however, there was not strong evidence for or against pathogenicity (Yurgelun_Gastroenterol_2015). In addition, two clinical diagnostic laboratories have classified this variant as one of uncertain significance. Taken together, this variant is classified as VUS.
Color RCV000562563 SCV000908358 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing

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