Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000629925 | SCV000750881 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-08-26 | criteria provided, single submitter | clinical testing | This variant has been reported in a family with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 525710). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu458*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002385976 | SCV002698039 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-03-04 | criteria provided, single submitter | clinical testing | The c.1373delT pathogenic mutation, located in coding exon 8 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1373, causing a translational frameshift with a predicted alternate stop codon (p.L458*). A different MSH2 alteration (c.1373T>G) resulting in the same truncation has been reported in multiple families with Lynch syndrome (Liu B et al. Cancer Res. 1994 Sep;54:4590-4; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835), including an individual with Muir-Torre phenotype whose sebaceous tumor demonstrated loss of MSH2 by IHC (Mangold E et al. J. Med. Genet. 2004 Jul;41:567-72). Additionally, ovarian and endometrial cancer specimens from individuals with the c.1373T>G MSH2 mutation demonstrated microsatellite instability and loss of MSH2 protein expression, while normal tissue from these patients was MSS with present MSH2 protein (Ichikawa Y et al. Cancer Genet. Cytogenet. 1999 Jul;112:2-8). Of note, this mutation is designated as "458 TTA to TGA," L458X, and "hMSH2/458/TTA to TGA" in published literature. 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, |
RCV003451492 | SCV004186975 | pathogenic | Lynch syndrome 1 | 2023-08-01 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |