Submissions for variant NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

dbSNP: rs267607885

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115474	SCV000149383	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in trans with a MLH1 pathogenic variant in an individual meeting Amsterdam criteria; however, the variant was shown to not segregate with disease (Mangold 2005, Pagenstecher 2006); Published functional studies demonstrate no damaging effect: shown to be non-pathogenic via oligonucleotide-directed mutation screening (Houlleberghs 2020); This variant is associated with the following publications: (PMID: 9419403, 22949387, 18383312, 15849733, 21404117, 16341550, 23760103, 23435383, 31784484)
Invitae	RCV000791373	SCV000254367	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 737 of the MLH1 protein (p.Asp737Val). This variant is present in population databases (rs267607885, gnomAD 0.0009%). This missense change has been observed to co-occur in individuals with a different variant in MLH1 that has been determined to be pathogenic (PMID: 16341550), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 90090). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 31784484). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000563079	SCV000662010	likely benign	Hereditary cancer-predisposing syndrome	2018-05-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000563079	SCV000684805	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000115474	SCV001500307	uncertain significance	not provided	2020-08-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894921	SCV004714834	uncertain significance	MLH1-related disorder	2024-01-11	criteria provided, single submitter	clinical testing	The MLH1 c.2210A>T variant is predicted to result in the amino acid substitution p.Asp737Val. This variant was reported, along with additional MLH1 variants, in individuals with non-polyposis colorectal cancer (Pagenstecher et al. 2006. PubMed ID: 16341550; Mangold et al. 2005. PubMed ID: 15849733). The significance of these reports is unclear given the uncertainty of the clinical significance of the additional variants and/or the variant phasing. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/90090/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997127	SCV004843297	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 737 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a HNPCC family who also had a pathogenic splice mutation in the same gene, in which the c.2210A>T variant is stated to not segregate with disease (PMID: 15849733, 16341550, 21404117). This variant has been identified in 1/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.