Submissions for variant NM_000249.4(MLH1):c.117-2A>G

dbSNP: rs267607712

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000780423	SCV000920458	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability > 0.99 (1.0)
Ambry Genetics	RCV000132299	SCV000187384	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The c.117-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the MLH1 gene. This mutation has been reported in numerous colorectal cancer patients whose tumors demonstrated loss of MLH1 expression and/or microsatellite instability and whose family histories met Amsterdam criteria (Casey G et al. JAMA. 2005 Feb;293(7):799-809; Rosty C et al. Fam. Cancer 2014 Dec;13(4):573-82; Guindalini RS et al. Gastroenterology 2015 Nov;149:1446-53; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471; Sarode VR et al. Arch Pathol Lab Med, 2019 10;143:1225-1233). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). In two studies, cDNA splicing analysis showed that this pathogenic mutation is associated with aberrant splicing causing a deletion of 5 bases at the beginning of exon 2 resulting in a premature stop codon (Casey G et al. JAMA. 2005 Feb;293(7):799-809; Thompson BA et al. Front Genet. 2020 Jul;11:798). 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). 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.
Invitae	RCV000200647	SCV000253784	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 individuals with clinical features of Lynch syndrome (PMID: 15713769, 25117503, 26248088, 27978560; Invitae). This variant is also known as IVS01-2A>G. ClinVar contains an entry for this variant (Variation ID: 142856). 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.
GeneDx	RCV000478069	SCV000568561	pathogenic	not provided	2017-03-06	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.117-2A>G or IVS1-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 1 of the MLH1 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in mulitple individuals with colorectal cancer, including at least three with personal and family histories fulfilling clinical Lynch syndrome criteria (Casey 2005, Rosty 2014, Guindalini 2015, Pearlman 2016). Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478069	SCV000601347	pathogenic	not provided	2017-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255219	SCV000917666	pathogenic	Hereditary nonpolyposis colon cancer	2020-08-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.117-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. Three predict the variant strengthens a cryptic exonic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251426 control chromosomes (gnomAD). c.117-2A>G has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Espenschied_2017, Pearlman_2017, Guindalini_2015, Casey_2005, Sarode_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters including an expert panel (InSiGHT) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003453096	SCV004188421	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	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.