Submissions for variant NM_000249.4(MLH1):c.546-2A>G

dbSNP: rs267607759

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075756	SCV000106768	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration, >2 MSI-H tumours, co-segregation with disease & MAF 0.00
Invitae	RCV000629970	SCV000750926	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 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 Lynch syndrome (PMID: 8521398, 10598809, 10732761, 20007843, 20223024, 24278394, 24851142, 27601186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90267). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202027	SCV001134316	pathogenic	not provided	2018-12-12	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV001024144	SCV001186112	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing	The c.546-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the MLH1 gene. This alteration is observed in at least one individual whose family history met Amsterdam criteria (Ambry internal data). This alteration has been reported in one Swedish early-onset HNPCC family with sarcoma, gastric cancer, and renal cancer, and was found to cause skipping of exon 7 (Tannergard et al. Cancer Res. 1995. 55, 6092-6096). This alteration has also been reported in a proband diagnosed with colon cancer at age 29 whose tumor showed microsatellite instability and absent MLH1 on immunohistochemistry. It segregated with disease in five family members (Dieumegard et al. Br. J. Cancer. 2000. 82(4), 871-880). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202027	SCV002558092	pathogenic	not provided	2022-07-28	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; Identified in individuals with personal and family history consistent with pathogenic variants in this gene (Tannergard et al., 1995; Liu et al., 1999; Dymerska et al., 2010; Lagerstedt-Robinson et al., 2016; Keranen et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27601186, 25525159, 8521398, 30572730, 20007843, 24122200, 10598809, 10471527, 10732761, 15713769, 24278394, 12658575, 24851142, 9288790, 12052501, 16199547, 20223024, 24362816)
Myriad Genetics, Inc.	RCV003452748	SCV004190031	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	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:12052501]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
CeGaT Center for Human Genetics Tuebingen	RCV000202027	SCV005041126	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MLH1: PVS1, PM2, PS4:Moderate, PP1
Mayo Clinic Laboratories, Mayo Clinic	RCV000202027	SCV000257104	pathogenic	not provided		no assertion criteria provided	research