Submissions for variant NM_000249.4(MLH1):c.791-1G>C

dbSNP: rs267607795

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075860	SCV000106877	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Color Diagnostics, LLC DBA Color Health	RCV001183311	SCV001349016	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 9 of the MLH1 gene. Functional RNA studies have shown that this variant causes exon 10 skipping, resulting in premature truncation (PMID: 22949379, 26247049, 29706640). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8571956, 2414824; DOI: 10.3343/lmo.2018.8.4.156). 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.
Invitae	RCV001388082	SCV001588929	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Based on a multifactorial likelihood algorithm using genetic, tumor, and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8571956). ClinVar contains an entry for this variant (Variation ID: 90369). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 9 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Mendelics	RCV002247470	SCV002517618	pathogenic	Muir-Torré syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452771	SCV004187335	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723644	SCV001956508	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723644	SCV001969136	pathogenic	not provided		no assertion criteria provided	clinical testing