ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4053_4081dup (p.Ter1361Leufs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491731 SCV000580103 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing The c.4053_4081dup29 variant, located in coding exon 10 of the MSH6 gene, results from a duplication of 29 nucleotides at position 4053, causing a translational frameshift with a predicted alternate stop codon (p.*1361Lext*3). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of MSH6, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 3 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. In addition, this alteration segregated with colorectal cancer and/or colon polyps in three related individuals whose family history met Amsterdam II criteria for Lynch syndrome (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001040497 SCV001204075 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-07-08 criteria provided, single submitter clinical testing This variant, c.4053_4081dup, disrupts the translational stop signal of MSH6 and is expected to extend the length of the protein by 3 additional amino acid residues. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428289). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000491731 SCV001348566 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-17 criteria provided, single submitter clinical testing

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