Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075544 | SCV000106534 | pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Coding sequence variation resulting in a stop codon |
| University of Washington Department of Laboratory Medicine, |
RCV000075544 | SCV000887328 | uncertain significance | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MLH1 NM_000249.3:c.2104-1_2104-2del has a 93.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. |
| Ambry Genetics | RCV002415544 | SCV002730446 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-01-23 | criteria provided, single submitter | clinical testing | The c.2104_2105delAG variant, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2104 to 2105, leading to an alternate stop codon (p.S702*). This variant has been reported in an individual diagnosed with MSI-high colorectal cancer meeting Amsterdam I criteria; MLH1 and MSH2 proteins were reported as present by immunohistochemistry (IHC) (Syngal S et al. JAMA, 1999 Jul;282:247-53; Wahlberg SS et al. Cancer Res., 2002 Jun;62:3485-92). This truncation occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 55 amino acids of the protein. However, structural analysis suggests that this alteration perturbs a known functional domain responsible for binding to and stabilizing PMS2 (Mohd AB et al. DNA Repair (Amst.), 2006 Mar;5:347-61). As such, this alteration is interpreted as likely pathogenic. |