ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2342C>T (p.Pro781Leu) (rs1553413710)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502336 SCV000592606 uncertain significance not specified 2012-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589271 SCV000695808 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2342C>T (p.Pro781Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant is found within the functional core domain of the protein (InterPro) and 4/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent from the large control population database ExAC (0/121254 control chromosomes). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
University of Washington Department of Laboratory Medicine,University of Washington RCV000664307 SCV000788239 pathogenic Lynch syndrome 2018-04-01 criteria provided, single submitter research The MSH6 gene variant designated as NM_000179.2:c.2342C>T (p.Pro781Leu) is classified as pathogenic. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.22 to 1, providing some evidence for pathogenicity (Thompson et al., 2003, PMID:2900794). Using computer predictions from MAPP and Polyphen2 algorithms we estimated a pretest probability of 90% supporting pathogenicity (Thompson et al, 2013, PMID:22949379). Combining pretest probability and segregation likelihood gives 92% probability of pathogenicity. In addition, this patient’s tumor had microsatellite instability and loss of MSH6, providing further evidence for pathogenicity. Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and cause Lynch syndrome-associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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