Submissions for variant NM_000249.4(MLH1):c.1558+1del

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV003450435	SCV004188332	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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.
All of Us Research Program, National Institutes of Health	RCV004011325	SCV004842730	likely pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide at the canonical splice site in intron 13 of the MLH1 gene. This intronic deletion may be rescued by the terminal guanine of exon 13, recreating the canonical donor site, but lead to the creation of a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. 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 Likely Pathogenic.