Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075086 | SCV000106075 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Variant causes splicing aberration predicted to produce truncated protein: full inactivation of variant allele |
| Ambry Genetics | RCV002390211 | SCV002702157 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-24 | criteria provided, single submitter | clinical testing | The c.1038G>C pathogenic mutation (also known as p.Q346H), located in coding exon 11 of the MLH1 gene, results from a G to C substitution at nucleotide position 1038. The amino acid change results in glutamine to histidine at codon 346, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in several Lynch syndrome families meeting Amsterdam I/II criteria and having tumors exhibiting loss of MLH1 protein by immunohistochemistry and high microsatellite instability (MSI-H) (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mangold E et al. J. Pathol., 2005 Dec;207:385-95; Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84). Using patient mRNA and allele-specific PCR, this variant caused skipping of exons 10 and 11 as well as activation of a cryptic splice donor site; no full-length transcript was expressed by the mutant allele (Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22). Two other disease-causing mutations, c.1038G>A (p.Q346Q) and c.1038G>T (p.Q346H) have been described in the same codon. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analyses. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV002243695 | SCV000038917 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2006-03-01 | no assertion criteria provided | literature only |