Submissions for variant NM_000249.4(MLH1):c.117-1G>A

dbSNP: rs587779950

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062062	SCV001226834	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 23224667, 24811117, 28874130; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 127610). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326810	SCV002633283	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-25	criteria provided, single submitter	clinical testing	The c.117-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the MLH1 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MLH1 and PMS2 expression by immunohistochemistry (Ambry internal data). Another alteration impacting the same acceptor site (c.117-2A>G) has been shown to have a similar impact on splicing and was identified in several individuals that met Amsterdam I/II criteria for Lynch syndrome, one of whom had a MSI-H colorectal tumor that demonstrated loss of MLH1 expression by IHC (Casey G et al. JAMA. 2005 Feb;293(7):799-809; Rosty C et al. Fam. Cancer 2014 Dec;13(4):573-82; Guindalini RS et al. Gastroenterology 2015 Nov;149:1446-53; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471; Sarode VR et al. Arch Pathol Lab Med, 2019 10;143:1225-1233; 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453039	SCV004185617	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998233	SCV005623545	pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The MLH1 c.117-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal MLH1 mRNA splicing. This variant has been identified in the published literature in individuals with colorectal cancer (PMID: 37965459 (2023)), Lynch syndrome (PMID: 26078562 (2015)), and an unspecified form of sarcoma (PMID: 34326862 (2021)). This variant has also been reported as a somatic variant in an individual with colorectal cancer (PMID: 24333619 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.