Submissions for variant NM_000249.4(MLH1):c.1668-2A>C

dbSNP: rs1559578422

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000777323	SCV000913185	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the -2 position of intron 14 of the MLH1 gene. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with Lynch syndrome (PMID: 27064304). 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.
Ambry Genetics	RCV000777323	SCV002709210	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-06	criteria provided, single submitter	clinical testing	The c.1668-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 15 in the MLH1 gene. This variant has been reported in an Australian Lynch syndrome family (Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31). Additionally, it has been identified in the germline of an individual with MSI-high colorectal cancer which showed loss of MLH1 protein on immunohistochemistry; this individual also fulfilled Amsterdam criteria (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453610	SCV004188859	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	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].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003594036	SCV004293465	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-21	criteria provided, single submitter	clinical testing	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: 631164). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 17095871, 27064304; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 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). For these reasons, this variant has been classified as Pathogenic.