Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075296 | SCV000106290 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability 0.95-0.99 |
| Ambry Genetics | RCV002399441 | SCV002706578 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-01 | criteria provided, single submitter | clinical testing | The p.L555P pathogenic mutation (also known as c.1664T>C), located in coding exon 14 of the MLH1 gene, results from a T to C substitution at nucleotide position 1664. The leucine at codon 555 is replaced by proline, an amino acid with similar properties. This alteration has been identified in individuals that met Amsterdam criteria for Lynch syndrome and their tumors demonstrated loss of both MLH1 and PMS2 on immunohistochemistry (IHC) (Ambry internal data; Farrell MP et al. Fam. Cancer, 2013 Dec;12:741-7). In an in vitro complementation assay, this variant demonstrated mismatch repair (MMR) activity similar to a known pathogenic mutation (Farrell MP et al. Fam. Cancer, 2013 Dec;12:741-7). Another alteration at the same position, p.L555R, has been reported as pathogenic due to its strong segregation with disease in a Lynch syndrome family with several individuals demonstrating high microsatellite instability (MSI-H) or loss of MLH1 and PMS2 on IHC in their tumors (Ambry internal data; Haraldsdottir S et al. Fam. Cancer, 2016 Apr;15:253-60; Roth RM et al. Am. J. Clin. Pathol., 2016 Jul;146:50-6; Haraldsdottir S et al. Genet. Med., 2016 Sep;18:863-8). Based on an internal structural assessment, p.L555P is anticipated to decrease protein stability. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003451046 | SCV004185861 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-21 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23712482, 30504929, 31784484]. This variant is expected to disrupt protein structure [Myriad internal data]. |