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 2019-02-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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 2019-12-25 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 2020-02-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175358 SCV000695849 likely benign not specified 2019-11-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3244C>T (p.Pro1082Ser) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251392 control chromosomes, exclusively reported within the East Asian subpopulation, at a frequency of 0.00065 (gnomAD). The observed variant frequency within East Asian control individuals is approximately 5-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 East Asian origin. The variant, c.3244C>T, has been reported in the literature in a Japanese colorectal cancer patient, however without strong evidence of causality (Terui_2013). The variant was also found in multiple Chinese individuals with personal- or family history of breast- or ovarian cancer (Wang_2019, Shao_2019). In one of these patients however, a co-occurring pathogenic variant has been reported (BRCA1 c.5521delA (p.Ser1841fs); Wang_2019) that could explain the phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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