Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000074837 | SCV000108049 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Ambry Genetics | RCV000223509 | SCV000275318 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | The c.3311_3312delTT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3311 to 3312, causing a translational frameshift with a predicted alternate stop codon (p.F1104Wfs*3). This variant was described in a proband with ovarian cancer at 49 years of age, whose family history included a father with rectal cancer at 80 years and paternal first cousin with endometrial cancer at 57 years. The proband's cousin was confirmed to be positive for the variant, which established obligate carrier status in the proband's father (Suchy J et al. J. Hum. Genet. 2002;47:529-31; Suchy J et al. Clin Genet. 2006 Jul;70:68-70). This variant was also reported in a man with MSI-H colorectal cancer diagnosed at age 22 and no family history; this individual also carried an alteration in HOXB13 (p.G84E) (Akbari MR et al. Cancer Epidemiol. 2013 Aug;37(4):424-7). The c.3311_3312delTT variant has also been reported in a 60 year old woman with three synchronous primary malignancies and whose family history met Amsterdam II criteria (Mendez LE et al. Gynecol Oncol Rep. 2016 Aug;17:29-32). 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. |
| Eurofins Ntd Llc |
RCV000202034 | SCV000331076 | pathogenic | not provided | 2016-02-04 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000630139 | SCV000751095 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-09-03 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Phe1104Trpfs*3) 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 present in population databases (rs267608092, gnomAD 0.003%). 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: 89370). For these reasons, this variant has been classified as Pathogenic. |
| Color Diagnostics, |
RCV000223509 | SCV000905456 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-05 | criteria provided, single submitter | clinical testing | This variant deletes 2 nucleotides in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 chromosomes 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. |
| Revvity Omics, |
RCV000202034 | SCV002017566 | pathogenic | not provided | 2019-05-05 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV000009490 | SCV004185680 | pathogenic | Lynch syndrome 5 | 2023-08-22 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Baylor Genetics | RCV003460681 | SCV004195558 | pathogenic | Endometrial carcinoma | 2023-08-25 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000202034 | SCV004221218 | pathogenic | not provided | 2021-09-14 | criteria provided, single submitter | clinical testing | This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, it has been described in individuals with endometrial cancer, ovarian cancer, and colorectal cancer in the published literature (PMID: 33746161 (2021), 30128536 (2018), 26648449 (2015), 23541221 (2013), 12376742 (2002)). Based on the available information, this variant is classified as pathogenic. |
| All of Us Research Program, |
RCV000074837 | SCV004835044 | pathogenic | Lynch syndrome | 2023-06-08 | criteria provided, single submitter | clinical testing | This variant deletes 2 nucleotides in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome-associated disease (PMID: 12376742, 16813607, 23541221, 27331139). This variant has been identified in 1/251428 chromosomes 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. |
| OMIM | RCV000009490 | SCV000029708 | pathogenic | Lynch syndrome 5 | 2002-01-01 | no assertion criteria provided | literature only | |
| Mayo Clinic Laboratories, |
RCV000202034 | SCV000257250 | pathogenic | not provided | no assertion criteria provided | research |