Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
University of Washington Department of Laboratory Medicine, |
RCV000758644 | SCV000887404 | pathogenic | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MLH1 NM_000249.3:c.790+5G>A has a 99.996% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without and with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. |
Myriad Genetics, |
RCV003453553 | SCV004186390 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-19 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8574961, 11781295]. |
Ambry Genetics | RCV004027160 | SCV005033270 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | The c.790+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 9 in the MLH1 gene. 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same donor site, c.790+5G>T, has been detected in reported in an individual with an MLH1-absent adenocarcinoma whose family history met Amsterdam criteria (Takahashi M et al. Fam. Cancer, 2012 Dec;11:559-64). The c.790+5G>T alteration was also shown to cause alternative splice site leading to exon 9 skipping by a pCAS ex vivo splicing assay (Tournier I et al. Hum Mutat, 2008 Dec;29:1412-24). Based on the majority of available evidence to date, the c.790+5G>A variant is likely to be pathogenic. |