Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075087 | SCV000106076 | 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 | RCV002390212 | SCV002698820 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-11-03 | criteria provided, single submitter | clinical testing | The c.1038G>T pathogenic mutation (also known as p.Q346H), located in coding exon 11 of the MLH1 gene, results from a G to T 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 identified in an individual with a microsatellite unstable colorectal carcinoma who fulfilled Amsterdam criteria for Lynch syndrome (Tang R et al. Clin. Genet., 2009 Apr;75:334-45). Based on analysis using a pCAS minigene in HeLa cells and RT-PCR of patient RNA, this alteration was shown to cause exon 11 skipping, activation of a cryptic splice donor site, and no production of full-length transcript from the variant allele (Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24). One disease-causing mutation, c.1038G>A (p.Q346Q) has 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 analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |