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

dbSNP: rs267607795

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168716	SCV000592377	pathogenic	Lynch syndrome	2016-08-12	criteria provided, single submitter	clinical testing
Invitae	RCV000692531	SCV000820358	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. RNA analysis provides insufficient evidence to determine the effect of this variant on MLH1 splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 188509). Disruption of this splice site has been observed in individual(s) with colon cancer (Invitae). It has also been observed to segregate with disease in related individuals. This sequence change affects an acceptor splice site in intron 9 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).
Ambry Genetics	RCV002415716	SCV002677271	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-21	criteria provided, single submitter	clinical testing	The c.791-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of the MLH1 gene. This alteration has been identified in several hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, two of which met Amsterdam I criteria (Ambry internal data; Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31). Other alterations impacting the same acceptor site (c.791-2A>G and c.791-2A>T) have been detected in individuals whose HNPCC/Lynch syndrome associated tumors demonstrated loss of both MLH1/PMS2 on immunohistochemistry and their family histories met Amsterdam I/II criteria for HNPCC/Lynch syndrome (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13; Sjursen et al. J Med Genet. 2010 Sep;47(9):579-85; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. 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 likely pathogenic.
Myriad Genetics, Inc.	RCV003454426	SCV004186305	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	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].