Submissions for variant NM_000249.4(MLH1):c.589-2A>G

dbSNP: rs267607767

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075780	SCV000106790	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberrations: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99.
GeneDx	RCV000212522	SCV000211093	pathogenic	not provided	2022-12-28	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); 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: 10422993, 19690142, 25345868, 28888541, 15713769, 25530820, 22949379, 7557107, 21671475, 22624972, 19267393, 12067992, 14970868, 10448273, 17192056, 26681312, 28944238, 29288294, 29228462, 25525159, 25980754, 30787465)
Ambry Genetics	RCV000160526	SCV000212755	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The c.589-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 of the MLH1 gene. This mutation has been reported in numerous Lynch syndrome families to date (Luce MC et al. Gastroenterology. 1995 Oct;109(4):1368-74; Viel A et al. Community Genet. 1998;1(4):229-36; Capozzi E et al. Eur. J. Cancer. 1999 Feb;35(2):289-95; Syngal S et al. JAMA. 1999 Jul 21;282(3):247-53; Casey G et al. JAMA. 2005 Feb 16;293(7):799-809; DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5(5):553-569). In addition, this alteration has been described as an American founder mutation (Tomsic J et al. Int. J. Cancer. 2012 May 1;130(9):2088-95). RNA studies have demonstrated that this alteration activates a cryptic acceptor site resulting in a transcript with a 4 base pair deletion, which is predicted to lead to a translational frameshift (Ambry internal data; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000524306	SCV000219008	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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: 7557107, 10422993, 21671475). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90291). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 7557107; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212522	SCV000601404	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal MLH1 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 30019097 (2019), 28944238 (2017), 25980754 (2015), 21671475 (2012)). Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000576331	SCV000677753	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-12-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160526	SCV000905465	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 7 of the MLH1 gene. Functional RNA studies have shown that this variant causes use of a cryptic splice site and skipping of exon 8, resulting in a frameshift and premature truncation (PMID: 7557107, 19267393, 22949379). This variant has been reported in multiple individuals affected with Lynch syndrome or Lynch syndrome-associated disease (PMID: 7557107, 8521398, 19267393, 21671475, 26681312, 29228462, 30019097). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075780	SCV000917650	pathogenic	Lynch syndrome	2018-04-17	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.589-2A>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: Five predict the variant abolishes a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Thompson_2013). The variant was absent in 246208 control chromosomes (gnomAD). The variant, c.589-2A>G has been reported in the literature in individuals affected with Lynch Syndrome (Syngal_1999, Susswein_2016, Tannergard_1995, Capozzi_1999). These data indicate that the variant is likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000212522	SCV003821584	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576331	SCV004018251	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15713769]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000576331	SCV004192996	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-06-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075780	SCV004847550	pathogenic	Lynch syndrome	2019-03-18	criteria provided, single submitter	clinical testing	The c.589-2A>G variant in MLH1 has been reported in >15 individuals with Lynch syndrome and segregated with disease in >15 affected relatives from multiple families (Luce 1995, Casey 2005, Tomsic 2012, DeRycke 2017). This variant is considered a founder variant (Tomsic 2015). This variant was absent from large population studies, but has been reported in ClinVar (Variation ID: 90291). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro studies demonstrate that this variant causes activation of a cryptic splice site, leading to a frameshift variant (Luce 1995, Arnold 2009). Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1_Strong, PS3_Moderate.
GeneReviews	RCV001804823	SCV002054096	not provided	Lynch syndrome 1		no assertion provided	literature only