Submissions for variant NM_000249.4(MLH1):c.1989+2T>C

dbSNP: rs1553664119

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564282	SCV000676019	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	clinical testing	The c.1989+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 17 in 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 donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was identified in a proband whose colorectal tumor demonstrated loss of PMS2 staining on immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV003144386	SCV003832596	likely pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451274	SCV004185583	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	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.
All of Us Research Program, National Institutes of Health	RCV004001191	SCV004838994	likely pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +2 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 functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer that displayed loss of PMS2 protein expression via immunohistochemistry analysis (ClinVar SCV000676019.4). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same canonical splice donor site, c.1989+1G>T, c.1989+1G>C and c.1989+1G>A, are known to be disease-causing (ClinVar variation ID: 89975, 89974, 89973). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.