Submissions for variant NM_000249.4(MLH1):c.2103+2T>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002424260	SCV002728374	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The c.2103+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 18 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. 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. 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, the impacted region is critical for protein function (Ambry internal data). This alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). A similar alteration affecting this same canonical splice site, c.2103+1G>A, has been reported in numerous individuals/families with Lynch syndrome, many of whom had tumor studies showing absent MLH1 protein expression on IHC (Wijnen J et al. Am. J. Hum. Genet. 1996 Feb;58(2):300-7; Berends MJ et al. Int. J. Cancer. 2001 May;92(3):398-403; Wagner A et al. Am. J. Hum. Genet. 2003 May;72(5):1088-100; Overbeek LI et al. Br. J. Cancer. 2007 May;96(10):1605-12; Skeldon SC et al. Eur. Urol. 2013 Feb;63(2):379-85; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV004007397	SCV004835440	likely pathogenic	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +2 position of intron 18 of the MLH1 gene. Splice site prediction tools suggest 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 result in an absent or disrupted protein product. This variant is likely to cause an in-frame skipping of exon 18 (114 base pairs-long; amino acids 664-701), and there are missense variants in the exon that are known to be disease-causing (ClinVar variation ID: 90014, 17099), supporting the functional and clinical importance of the region that may be impacted by this variant. This variant has not been reported in individuals affected with MLH1-related disorders 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 donor site, c.2103+1G>A, c.2103+1G>C, c.2103+1G>T, c.2103+2T>G and c.2103+2T>A, are known to be disease-causing (ClinVar variation ID: 90044, 90045, 90046, 1785949, 1785947). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.