ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3439-10T>A (rs730881819)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580444 SCV000685403 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Counsyl RCV000410182 SCV000489332 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-09-19 criteria provided, single submitter clinical testing
GeneDx RCV000160728 SCV000211362 benign not specified 2014-07-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000160728 SCV000917735 uncertain significance not specified 2018-06-08 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3439-10T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.9e-05 in 277170 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3439-10T>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, one database (UMD) cites the variant as having normal splicing via RT-PCR, without evidence to independently evaluate (UMD cites the variant in 1 individual with a classification of "likely neutral" with MSI-H, MLH1+, MSH2-, MSH6-, PMS2+ tumor, RT-PCR: normal splicing and Amsterdam II + as a description (unpublished data)). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with classifications of VUS and likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000227561 SCV000283805 likely benign Hereditary nonpolyposis colon cancer 2017-12-24 criteria provided, single submitter clinical testing

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