ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.790+5G>A

dbSNP: rs267607771
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington 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, Inc. 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.

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