Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075551 | SCV000106548 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon with functional domain |
| Ambry Genetics | RCV002415546 | SCV002729158 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-20 | criteria provided, single submitter | clinical testing | The p.W712* pathogenic mutation (also known as c.2136G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2136. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45 amino acids of the protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been described in several HNPCC individuals, including some whose tumors demonstrated high microsatellite instability and/or loss of MLH1 on immunohistochemistry, and family histories meeting Amsterdam I/II criteria (Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Piñol V et al. JAMA, 2005 Apr;293:1986-94; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72). Functional analysis determined that this alteraton has reduced interaction with hPMS2 (Kondo E et al. Cancer Res, 2003 Jun;63:3302-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003451109 | SCV004189895 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-25 | 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. |
| Constitutional Genetics Lab, |
RCV001249996 | SCV001423897 | pathogenic | Lynch-like syndrome | 2019-07-01 | no assertion criteria provided | clinical testing |