Total submissions: 3
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, |
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. |