ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3851C>T (p.Thr1284Met) (rs63750836)

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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 RCV000131709 SCV000186747 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131709 SCV000685455 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000662523 SCV000785081 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000759868 SCV000565237 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3851C>T at the cDNA level, p.Thr1284Met (T1284M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in an individual with a microsatellite stable (MSS) colon tumor, in an individual with pancreatic cancer, and in another individual whose personal and/or family history was suggestive of Lynch syndrome (Chan 1999, Yan 2007, Young 2018). A subcellular localization assay demonstrated no measurable difference between MSH6 Thr1284Met and wild type, suggesting this variant does not disrupt nuclear localization (Belvederesi 2012). MSH6 Thr1284Met was observed at an allele frequency of 0.11% (35/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH6 Thr1284Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074944 SCV000108158 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524191 SCV000259281 likely benign Hereditary nonpolyposis colon cancer 2017-12-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454725 SCV000539710 uncertain significance not specified 2016-06-23 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: ClinVar: 2 VUS (including expert panel, no new evidence since expert classification)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759868 SCV000889498 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing

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