ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3172+1G>T (rs587779255)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074809 SCV000108020 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000627710 SCV000253777 pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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). This variant has been reported in individuals affected with Lynch syndrome (PMID: 20487569, Invitae). ClinVar contains an entry for this variant (Variation ID: 89344). 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.
Ambry Genetics RCV000565688 SCV000676108 pathogenic Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing The c.3172+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the MSH6 gene. This alteration was reported in a colorectal cancer patient whose tumor showed isolated loss of MSH6 by immunohistochemistry and whose family history met Amsterdam II criteria, and in a Japanese patient diagnosed with ovarian and endometrial cancer (Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Hirasawa A et al. Oncotarget. 2017 Nov 28;8(68):112258-112267). 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.
Color Health, Inc RCV000565688 SCV000903163 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194394 SCV001363902 likely pathogenic Hereditary nonpolyposis colon cancer 2019-10-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3172+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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 243746 control chromosomes (gnomAD). c.3172+1G>T has been reported in the literature in individuals affected with ovarian cancer or Lynch syndrome (Hirasawa_2017, Talseth-Palmer_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions including an expert panel, InSiGHT, (evaluation after 2014) cites the variant twice as likely pathogenic and twice as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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