ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074858 SCV000108070 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
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.
Ambry Genetics RCV000491481 SCV000580140 pathogenic Hereditary cancer-predisposing syndrome 2018-01-24 criteria provided, single submitter clinical testing 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074858 SCV000592643 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215652 SCV000601573 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing
Color RCV000491481 SCV000690355 pathogenic Hereditary cancer-predisposing syndrome 2020-03-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074858 SCV000695865 pathogenic Lynch syndrome 2019-03-12 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3439-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246190 control chromosomes (gnomAD). This variant has been reported in the literature in individuals affected with Lynch syndrome and Prostate cancer (Talseth-Palmer_2010, Rosty_2014, Chubb_2015, Sjursen_2016, Chubb_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000629776 SCV000750732 pathogenic Hereditary nonpolyposis colon cancer 2019-08-11 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 observed 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.