ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3986C>T (p.Ser1329Leu) (rs199594809)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115429 SCV000186415 likely benign Hereditary cancer-predisposing syndrome 2017-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Structural Evidence
Color RCV000115429 SCV000902787 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000212693 SCV000149338 likely benign not specified 2017-08-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000212693 SCV000695905 uncertain significance not specified 2019-05-07 criteria provided, single submitter clinical testing MSH6 c.3986C>T (p.Ser1329Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, two in silico studies predicted the variant being benign/neutral (Terui_2013, Ali_2012). The variant allele was found at a frequency of 4.5e-05 in 246306 control chromosomes, predominantly at a frequency of 9.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3986C>T, has been reported in the literature in individuals affected with colorectal cancer (Steinke_2008, Kraus_2014, Graham_2015) who displayed normal IHC staining patterns, had microsatellite stable (MSS) analysis and/or did not fulfill the classical diagnostic criteria for Lynch syndrome (example, the revised Bethesda criteria, Kraus_2014 and Steinke_2008). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=3), likely benign (n=2)). An expert panel (InSIGHT) has submitted a classification for this variant in ClinVar before 2014 (in 2013) as likely benign citing a multifactorial likelihood analysis posterior probability 0.001-0.049. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074965 SCV000108180 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524202 SCV000254323 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1329 of the MSH6 protein (p.Ser1329Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs199594809, ExAC 0.009%). This variant has been reported in individuals with suspected Lynch syndrome (PMID: 18301448). ClinVar contains an entry for this variant (Variation ID: 89497). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914, 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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.
Mendelics RCV000074965 SCV000837927 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212693 SCV000601595 uncertain significance not specified 2016-09-23 criteria provided, single submitter clinical testing

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