Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| University of Washington Department of Laboratory Medicine, |
RCV000075853 | SCV000887402 | pathogenic | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MLH1 NM_000249.3:c.790+3A>T has a 99.96% 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 | RCV002415548 | SCV002676917 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-15 | criteria provided, single submitter | clinical testing | The c.790+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 9 in the MLH1 gene. This variant, designated IVS9+3A>T, was reported in a patient whose colon tumor was MSI-H (Gille JJ et al. Br J Cancer, 2002 Oct;87:892-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Other alterations impacting the same donor site (c.790+4A>G and c.790+4A>T) have been detected in patients meeting Amsterdam criteria, several of whose tumors demonstrated loss of MLH1 staining on immunohistochemistry and/or microsatellite instability (Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Lamberti C et al. Gut, 1999 Jun;44:839-43; Bianchi F et al. Fam Cancer, 2011 Mar;10:27-35; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |