Submissions for variant NM_000249.4(MLH1):c.1990-1G>C

dbSNP: rs267607884

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772614	SCV000905795	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-27	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the -1 position of intron 17 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to disrupt the PMS2/MLH3/PMS1 interacting domain. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site (c.1990-1G>A, c.1990-1G>T) are considered to be disease-causing (ClinVar variation ID: 89985, 89986), suggesting that the reference sequence at this splice site is important for normal RNA splicing. Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000772614	SCV001174619	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The c.1990-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 18 of the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MLH1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036557	SCV001199927	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-04-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 628266). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15365996; 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 17 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).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310199	SCV001499800	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477757	SCV002774355	pathogenic	not provided	2021-06-19	criteria provided, single submitter	clinical testing	Final score = 7 (Pathogenic) MLH1|1990-1G>C, a predicted loss-of-function variant with dominant inheritance: This variant disrupts a canonical splice site and interferes with normal mRNA splicing. Another variant at this canonical splice site is also pathogenic in the internal database (c.1990-1G>A) +1: [PP4+PM2]-modified, Found in at least one symptomatic patient, and not found in general population data. (Identified in testing individual whose mother and maternal grandmother were positive for the variant and affected. ) No publications were found during Google and Google Scholar searches.