Submissions for variant NM_000249.4(MLH1):c.1039-2A>G

dbSNP: rs267607815

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075090	SCV000106083	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075090	SCV000887405	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1039-2A>G has a 99.98% 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514335	SCV003525103	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 15849733, 19669161; internal data). ClinVar contains an entry for this variant (Variation ID: 89621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003137609	SCV003806618	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-12-29	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.
PreventionGenetics, part of Exact Sciences	RCV003390766	SCV004110107	likely pathogenic	MLH1-related disorder	2023-06-20	criteria provided, single submitter	clinical testing	The MLH1 c.1039-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in at least two individuals with hereditary non-polyposis colorectal cancer (HNPCC) (Mangold et al. 2005. PubMed ID: 15849733; Betz et al. 2010. PubMed ID: 19669161). mRNA studies showed that this variant results in the skipping of exon 12 leading to a frameshift and premature protein termination (Betz et al. 2010. PubMed ID: 19669161). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89621/). Variants that disrupt the consensus splice acceptor site in MLH1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
GeneDx	RCV003441739	SCV004168658	likely pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: exon skipping resulting in truncated protein (Betz et al., 2010); Observed in at least one family reported to have features consistent with Lynch syndrome (Mangold et al., 2005); This variant is associated with the following publications: (PMID: 25525159, 19669161, Castillejo2016[article], 15849733, 29887214)