Submissions for variant NM_000249.4(MLH1):c.1409+1G>C

dbSNP: rs267607825

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075193	SCV000106183	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causing splicing aberration (not quanitified), 1 MSI-H tumour & 1 tumour with MLH1 immunoloss, co-segregation with disease & absent in 1000 genomes.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281908	SCV002570539	pathogenic	Hereditary nonpolyposis colon cancer	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1409+1G>C 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: Four predict the variant abolishes a 5 splicing donor site. The variant was absent in 250196 control chromosomes (gnomAD). c.1409+1G>C has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Peltomaki_1997, Holmberg_1998, Kurzawski_2002, Buchanan_2017). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002390216	SCV002697828	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-30	criteria provided, single submitter	clinical testing	The c.1409+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 12 of the MLH1 gene. 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. (Holmberg M et al. Hum. Mutat., 1998;11:482). (Schweizer P et al. Cancer Res., 2001 Apr;61:2813-5). (Kurzawski G et al. Clin. Genet., 2006 Jan;69:40-7).
Invitae	RCV002513800	SCV003525104	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89719). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 9322509; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 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).
Myriad Genetics, Inc.	RCV003451025	SCV004186418	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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. 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].