ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2764C>T (p.Arg922Ter) (rs587779246)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074779 SCV000107989 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000491845 SCV000580132 pathogenic Hereditary cancer-predisposing syndrome 2017-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000074779 SCV000695829 pathogenic Lynch syndrome 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2764C>T (p.Arg922X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3013C>T, p.Arg1005X; c.3052_3053delCT, p.Leu1018fsX4; c.3103C>T, p.Arg1035X; c.3202C>T, p.Arg1068X). The variant of interest has been found in a large, broad control population, ExAC in 1/120734 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). This variant was found in multiple patients with CRC (Bonadona_2011, Sjursen_2015) and also in tumor samples (Han_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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