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
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 2019-12-13 criteria provided, single submitter clinical testing The c.3439-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide before coding exon 6 of the MSH6 gene. This mutation has been reported in individuals with early onset colon cancer and suspected Lynch syndrome (Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32; Cruz-Correa M et al. Fam. Cancer 2015 Sep;14:415-25). In one family fulfilling Amsterdam II criteria, the proband was diagnosed with colorectal cancer at 54 that demonstrated loss of MSH6 protein by immunohistochemistry; other cancers in the family included colon, ovarian, and endometrial (Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5). This variant has also been identified in several individuals whose Lynch syndrome associated tumors demonstrated isolated loss of MSH6 on immunohistochemistry (IHC) (Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215652 SCV000601573 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491481 SCV000690355 pathogenic Hereditary cancer-predisposing syndrome 2021-01-19 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the -1 position of intron 5 of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in individuals and families affected with Lynch syndrome-associated cancer (PMID: 20487569, 25782445, 27064304, 27329137) and an individual from a colon cancer family registry affected with prostate cancer (PMID: 25117503). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 colorectal neoplasms 2020-10-05 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000215652 SCV000592643 uncertain significance not provided no assertion criteria provided clinical testing

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