Submissions for variant NM_000249.4(MLH1):c.1732-2A>G

dbSNP: rs267607852

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075335	SCV000106332	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506870	SCV000601364	likely pathogenic	not provided	2017-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV001386351	SCV001586542	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Ala586Asp) have been determined to be pathogenic (PMID: 16395668, 30998989; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 24090359). ClinVar contains an entry for this variant (Variation ID: 89861). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 8571956, 24090359; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 15 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Ambry Genetics	RCV002399446	SCV002713767	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-07	criteria provided, single submitter	clinical testing	The c.1732-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 16 in the MLH1 gene. This variant has been identified in at least one proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability (MSI-H) and/or loss of both MLH1/PMS2 protein expression on immunohistochemistry (IHC) (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). 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 and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451058	SCV004187401	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	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.