ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3439-1G>T (rs587779263)

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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 RCV000491481 SCV000580140 pathogenic Hereditary cancer-predisposing syndrome 2018-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000491481 SCV000690355 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074858 SCV000592643 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
GeneDx RCV000215652 SCV000279241 pathogenic not provided 2016-03-03 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3439-1G>T or IVS5-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 5 of the MSH6 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in an individual with colorectal cancer from a large kindred affected by colorectal and other Lynch-related cancers whose tumor demonstrated loss of MSH6 protein expression (Talseth-Palmer 2010). MSH6 c.3439-1G>T has also been reported in another individual with a personal and family history of colorectal cancer as well as a patient with prostate cancer whose family history met Amsterdam criteria (Rosty 2014, Chubb 2015). While the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014), this classification did not take into account evidence from any of these literature reports. Based on currently available information, we consider MSH6 c.3439-1G>T to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074858 SCV000695865 pathogenic Lynch syndrome 2017-08-23 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3439-1G>T variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121346 control chromosomes. A publication, Talseth-Palmer_2010, identified the variant in 1 affected individual. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074858 SCV000108070 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical acceptor splice site
Invitae RCV000629776 SCV000750732 pathogenic Hereditary nonpolyposis colon cancer 2018-11-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been reported in individuals and families affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 20487569, 5559809, 10537275, 20028993, 25980754, Invitae). ClinVar contains an entry for this variant (Variation ID: 89390). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215652 SCV000601573 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing

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