ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2959A>G (p.Thr987Ala) (rs746631156)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166654 SCV000217459 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166654 SCV000906808 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
Counsyl RCV000662610 SCV000785259 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-06-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764425 SCV000895482 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000767216 SCV000279343 uncertain significance not provided 2016-08-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2959A>G at the cDNA level, p.Thr987Ala (T987A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr987Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr987Ala occurs at a position that is not conserved and is located within domain IV of the MutS domain (Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Thr987Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000214752 SCV000917753 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2959A>G (p.Thr987Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) and the DNA mismatch repair protein MutS, clamp (IPR007861) domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 214668 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2959A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000198691 SCV000254301 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 987 of the MSH6 protein (p.Thr987Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs746631156, 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: 186981). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000214752 SCV000539718 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a Max MAF of 0.002% (1 allele). The AA at this posistion is not conserved - 6 mammals and 2 non-mammals have an Ala at this position. This variant has not been reported in affected individuals. It is classified as VUS in ClinVar by Ambry, Invitae, and GeneDx (2 stars). The variant is predicted to be benign by prediction tools.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214752 SCV000601549 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing

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