ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1368G>A (p.Trp456Ter)

dbSNP: rs1572722737
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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 RCV001011198 SCV001171493 pathogenic Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing The p.W456* pathogenic mutation (also known as c.1368G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1368. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. A similar mutation which causes the same protein truncation, c.1367G>A (p.W456*), has been reported in two unrelated endometrial cancer patients, including one who had a synchronous ovarian cancer diagnosis (Egoavil C et al. PLoS ONE, 2013 Nov;8:e79737). In addition to the clinical data presented in the literature, p.W456* (c.1368G>A) is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001047126 SCV001211062 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-04-28 criteria provided, single submitter clinical testing A different variant (c.1367G>A) giving rise to the same protein effect observed here (p.Trp456*) has been determined to be pathogenic (PMID: 24244552, 26270727). This suggests that this variant is also likely to be causative of disease. This variant has not been reported in the literature in individuals with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp456*) 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). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV003455070 SCV004185713 pathogenic Lynch syndrome 5 2023-08-14 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.

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