ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3244C>T (p.Pro1082Ser) (rs186240214)

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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 RCV000129766 SCV000184575 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000586138 SCV000211316 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3244C>T at the cDNA level, p.Pro1082Ser (P1082S) at the protein level, and results in the change of a Proline to a Serine (CCG>TCG). This variant was observed in a patient with sporadic colorectal cancer whose tumor was microsatellite stable, demonstrated microsatellite stability, loss of MLH1and PMS2 expression on immunohistochemistry, and was positive for MLH1 promoter hypermethylation (Terui 2013). MSH6 Pro1082Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 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 Pro1082Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409325 SCV000487794 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-24 criteria provided, single submitter clinical testing
Invitae RCV000464994 SCV000551272 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1082 of the MSH6 protein (p.Pro1082Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs186240214, ExAC 0.07%). This variant has been reported in the literature in an individual affected with Lynch syndrome (PMID: 24100870). ClinVar contains an entry for this variant (Variation ID: 141299). An algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change is likely to be tolerated. However, this prediction has 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.
Fulgent Genetics,Fulgent Genetics RCV000515187 SCV000611404 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000129766 SCV000685370 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586138 SCV000695849 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3244C>T (p.Pro1082Ser) variant located in the DNA mismatch repair protein MutS domain causes a missense change involving a conserved nucleotide with 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 6/121340 (1/20242), predominantly in the East Asian cohort, 6/8644 (1/1440). This frequency is about 5 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. This variant was reported in a Japanese CRC patient without strong evidence for causality, in addition, the pt was indicated to have loss of protein expression for MLH1 and PMS2, along with hypermethylation of MLH1, suggesting these played a key role in the onset of disease, not the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence to independently evaluate. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS) - Possibly Benign" until additional information becomes available.

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