Submissions for variant NM_000249.4(MLH1):c.678-1G>A

dbSNP: rs267607784

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758642	SCV000887401	likely pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.678-1G>A has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002360870	SCV002663746	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing	The c.678-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 9 of the MLH1 gene. This alteration has been reported in a patient diagnosed with synchronous colon cancers at age 49y demonstrating microsatellite instability and mismatch repair deficiency (Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095). This alteration has also been detected as somatic in multiple colon cancers and has been classified as likely pathogenic using a Bayesian model that incorporates tumor mutation data (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Other alterations at this canonical splice acceptor site have demonstrated aberrant splicing and have been reported in Lynch syndrome patients who tumors demonstrated microsatellite instability and loss of MLH1/PMS2 by IHC (Thompson BA et al. Hum. Mutat., 2013 Jan;34:200-9; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001724148	SCV004025960	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing	PVS1, PM2_SUP
Myriad Genetics, Inc.	RCV003453552	SCV004185639	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724148	SCV001958908	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724148	SCV001965922	pathogenic	not provided		no assertion criteria provided	clinical testing