ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3952A>T (p.Arg1318Ter)

dbSNP: rs1572747685
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826178 SCV000967717 likely pathogenic Lynch syndrome 2017-12-14 criteria provided, single submitter clinical testing The p.Arg1318X variant in MSH6 has not been previously reported in individuals w ith MSH6-associated cancers and was absent from large population studies. This n onsense variant leads to a premature termination codon at position 1318. This te rmination codon occurs within the terminal 50 bases of the second to last exon a nd is more likely to escape nonsense mediated decay (NMD), resulting in a trunca ted protein. Truncating variants downstream of this variant have been reported i n individuals with Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1318X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2.
Ambry Genetics RCV002352477 SCV002621041 pathogenic Hereditary cancer-predisposing syndrome 2019-08-27 criteria provided, single submitter clinical testing The p.R1318* pathogenic mutation (also known as c.3952A>T), located in coding exon 9 of the MSH6 gene, results from an A to T substitution at nucleotide position 3952. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV003453759 SCV004188228 pathogenic Lynch syndrome 5 2023-08-28 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Invitae RCV003594042 SCV004320540 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-08-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 667409). This premature translational stop signal has been observed in individual(s) with lymphoma (PMID: 33809641). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1318*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).

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