ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.380+1G>T

dbSNP: rs267607745
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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 RCV000758639 SCV000887398 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.380+1G>T has a 99.8% 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 RCV002352267 SCV002622778 pathogenic Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing The c.380+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the MLH1 gene. Other mutations at this canonical donor site have been detected in multiple Lynch syndrome patients whose tumors demonstrated microsatellite instability and/or loss of MLH1/PMS2 on IHC (Bartosova Z et al. Hum Mutat. 2003 Apr;21(4):449; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mangold E et al. J. Pathol., 2005 Dec;207:385-95; Schofield L et al. Int. J. Cancer, 2009 Mar;124:1097-102). This alteration has also been detected as somatic in conjunction with a second somatic hit in a patient diagnosed with colon cancer demonstrating microsatellite instability and loss of MLH1/PMS2 (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Myriad Genetics, Inc. RCV003453550 SCV004185805 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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