ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4081T>C (p.Ter1361Gln)

gnomAD frequency: 0.00001  dbSNP: rs765098678
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486271 SCV000565243 uncertain significance not provided 2023-03-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Normal stop codon changed to a glutamine codon, leading to the addition of 29 amino acids at the C-terminus; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29703253)
Ambry Genetics RCV000562452 SCV000676113 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-09 criteria provided, single submitter clinical testing The c.4081T>C variant (also known as p.*1361Qext*29), located in coding exon 10 of the MSH6 gene, results from a T to C substitution at nucleotide position 4081. This alteration disrupts the stop codon of the MSH6 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 29 amino acids. The exact functional effect of the additional amino acids is unknown. This alteration was observed in the TCGA colorectal adenocarcinoma data set, which was used to represent sporadic cancer in a study of patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 May;382:2103-2116). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000694136 SCV000822567 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-07-06 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the MSH6 mRNA. It is expected to extend the length of the MSH6 protein by 29 additional amino acid residues. This variant is present in population databases (rs765098678, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 418334). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 Diagnostics, LLC DBA Color Health RCV000562452 SCV000908446 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-03 criteria provided, single submitter clinical testing This variant changes the translational stop signal of the MSH6 gene to glutamine. Translation read-through is expected to extend the length of the MSH6 protein by 29 additional amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV004002248 SCV004835206 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This variant changes the translational stop signal of the MSH6 gene to glutamine. Translation read-through is expected to extend the length of the MSH6 protein by 29 additional amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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