Submissions for variant NM_000249.4(MLH1):c.116+1G>A

dbSNP: rs267607709

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075127	SCV000106118	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709737	SCV000840003	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-05-24	criteria provided, single submitter	clinical testing	This c.116+1G>A variant in the MLH1 gene has been reported in one patient with colorectal cancer diagnosed before 30 years of age [PMID 9718327]. This variant has not been observed in our patient database nor has been detected in the ExAC database. This variant was however reported in ClinVar and was classified as likely pathogenic in 2013 by an expert panel (SCV000106118.2). This variant affects the invariant donor splice site of intron 1 of the MLH1 gene. While not validated for clinical use, computer-based algorithms predict this c.116+1G>A change to disrupt the splice site. This variant is thus classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284001	SCV001469542	pathogenic	not provided	2019-11-25	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal MLH1 mRNA splicing and has been reported in a case each of colorectal and breast cancer (PMID: 9718327 (1998), 30362666 (2018)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV001294059	SCV001482844	pathogenic	Mismatch repair cancer syndrome 1	2019-05-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9718327]
Ambry Genetics	RCV002354257	SCV002619506	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-30	criteria provided, single submitter	clinical testing	The c.116+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the MLH1 gene. This alteration has been reported in a Scottish individual diagnosed with MSI-H colorectal cancer under age 30 and having a family history of colorectal cancer in one relative (Farrington SM et al. Am. J. Hum. Genet., 1998 Sep;63:749-59) and has also been reported in a female diagnosed with MSI-L colorectal cancer at age 19 (Barnetson RA et al. N. Engl. J. Med., 2006 Jun;354:2751-63). This alteration has been reported as IVS1+1G>A in published literature. 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. 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514337	SCV003525125	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 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 individual(s) with colon cancer and/or Lynch syndrome (PMID: 9718327, 22120844; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89656). 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.	RCV000709737	SCV004190040	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	criteria provided, single submitter	clinical testing	This variant is considered 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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769].
All of Us Research Program, National Institutes of Health	RCV000075127	SCV005427818	pathogenic	Lynch syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This variant causes a G to A change at the +1 position of intron 1 of the MLH1 protein. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing, and would result in out-of-frame skipping of exon 1 leading to a premature stop signal. A functional RNA study done using RT-PCR of patient RNA has reported that this variant causes aberrant splicing, but the impact was not specified (PMID: 32849802). This variant has been reported in multiple individuals affected with Lynch syndrome-associated disease, and tumor data from these individuals has demonstrated microsatellite instability and/or loss of MLH1 protein expression via immunohistochemistry analysis (PMID: 9718327, 16807412, 27398995, 35713195, 37244485). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.