Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000551310 | SCV000624647 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-08-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln475*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 33414168). ClinVar contains an entry for this variant (Variation ID: 455135). For these reasons, this variant has been classified as Pathogenic. |
| Color Diagnostics, |
RCV001189638 | SCV001356965 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-15 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Ambry Genetics | RCV001189638 | SCV002702700 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-27 | criteria provided, single submitter | clinical testing | The p.Q475* pathogenic mutation (also known as c.1423C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1423. This changes the amino acid from a glutamine to a stop codon within coding exon 4. Another alteration, c.1422_1423delGCinsAT, that leads to same premature truncation (p.Gln475X) was detected in a patient with colorectal cancer at age 31 that demonstrated high microsatellite instability and loss of MSH6 staining on immunohistochemistry (Win AK et al. J Med Genet, 2011 Aug;48:530-4), and has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Hum Mutat, 2013 Jan;34:200-9). In addition to the clinical data presented in the literature, this alteration 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. |
| Myriad Genetics, |
RCV003449501 | SCV004185591 | 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. |
| Institute of Human Genetics, |
RCV003449501 | SCV005368053 | pathogenic | Lynch syndrome 5 | 2024-04-03 | criteria provided, single submitter | clinical testing | Criteria applied: PVS1,PM2_SUP,PP4 |