Submissions for variant NM_000249.4(MLH1):c.1039-1G>T

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002396935	SCV002697011	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The c.1039-1G>T intronic pathogenic variant results from a G to T substitution one nucleotide before coding exon 12 of the MLH1 gene. This variant has been reported in one HNPCC/Lynch syndrome family (Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10). This variant was also identified in individuals whose HNPCC/Lynch-associated tumors displayed loss of both MLH1/PMS2 on immunohistochemistry (IHC) and had family histories that met Amsterdam I/II criteria for HNPCC/Lynch syndrome (Ambry internal data). In a cohort study of 1231 colorectal cancer cases, this variant was reported once and was not identified in the control group made up of 93 individuals (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another pathogenic variant at the same position, c.1039-1G>A, was reported in multiple Finnish individuals with colorectal cancer and family histories of HNPCC/Lynch-associated cancers some of which displayed loss of MLH1 on IHC (Peltomäki P et al. Gastroenterology 1997 Oct;113:1146-58; Holmberg M et al. Hum. Mutat. 1998;11:482; Kuismanen SA et al. Am. J. Pathol. 2000 May;156:1773-9; Bala S et al. Cancer Res. 2001 Aug;61:6042-5; Peltomäki P et al. Fam. Cancer 2001;1:9-15; Schweizer P et al. Cancer Res., 2001 Apr;61:2813-5). This nucleotide position is highly conserved in available vertebrate species. 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). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467460	SCV002762818	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV002467460	SCV004189196	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017932	SCV004848303	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.1039-1G>T variant in MLH1 has been reported in at least 1 individual with Lynch syndrome (Bonadona 2011). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Another variant at this site (c.1039-1G>A) has been shown to segregate with disease in a large Finnish kindred (Holmberg 1998, Schweizer 2001). 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, PM2.