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 2020-03-17 criteria provided, single submitter clinical testing The p.P1082S variant (also known as c.3244C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3244. The proline at codon 1082 is replaced by serine, an amino acid with similar properties. This variant was identified in a 54 year-old Japanese individual with MSI-H colon cancer that demonstrated loss of MLH1 and PMS2 on IHC analysis and MLH1 promoter hypermethylation; his family history was significant for a father with stomach cancer at age 59 (Terui H et al. Oncol. Rep. 2013 Dec;30:2909-16). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 colorectal neoplasms 2020-09-23 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 with clinical features of Lynch syndrome (PMID: 24100870) and in an individual affected with breast cancer (PMID: 30982232). 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 Health, Inc RCV000129766 SCV000685370 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-22 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 1082 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with colorectal cancer (PMID: 24100870, 33294277) and at least six suspected hereditary breast and ovarian cancer families (PMID: 30982232, 31742824). In the colorectal cancer cases, one individual had a pathogenic MLH1 covariant and in a second case the methylation of MLH1 was detected along with the loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 33294277). This variant also has been detected in a pancreatic cancer case-control study in which it was found in five unaffected control individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 13/282780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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