Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000162487 | SCV000212863 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-09-21 | criteria provided, single submitter | clinical testing | The p.Q451* pathogenic mutation (also known as c.1351C>T), located in coding exon 8 of the MSH2 gene, results from a C to T substitution at nucleotide position 1351. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been previously reported in patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated loss of MSH2 staining by immunohistochemistry (IHC) with family histories meeting Amsterdam criteria (Parc, Y et al. J Med Genet. 2003 Mar;40(3):208-13; Canard G et al. Ann. Surg. Oncol., 2012 Mar;19:809-16; Chubb D et al. Nat Commun, 2016 06;7:11883; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Huang M et al. Sci Rep, 2021 Jun;11:11712; Post CCB et al. J Natl Cancer Inst, 2021 Sep;113:1212-1220; Ambry internal data). 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. |
| Labcorp Genetics |
RCV000629700 | SCV000750656 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-09-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln451*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12624141, 21879275). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 183761). For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003454394 | SCV004188121 | pathogenic | Lynch syndrome 1 | 2023-08-01 | 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. |
| Mayo Clinic Laboratories, |
RCV000202208 | SCV000257137 | pathogenic | not provided | no assertion criteria provided | research |