Submissions for variant NM_000249.4(MLH1):c.2242G>C (p.Asp748His)

gnomAD frequency: 0.00001  dbSNP: rs374380262

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464953	SCV000543657	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 748 of the MLH1 protein (p.Asp748His). This variant is present in population databases (rs374380262, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 405434). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000776448	SCV000911980	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 748 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 not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251302 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.
Ambry Genetics	RCV000776448	SCV001175676	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	The p.D748H variant (also known as c.2242G>C), located in coding exon 19 of the MLH1 gene, results from a G to C substitution at nucleotide position 2242. The aspartic acid at codon 748 is replaced by histidine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153596	SCV003842969	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2022-12-19	criteria provided, single submitter	clinical testing	The MLH1 c.2242G>C (p.Asp748His) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In a case-control study, this variant was detected in 0 of 165 individuals with colorectal cancer and/or polyposis and 1 of 2512 control individuals (PMID: 30267214). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004000666	SCV004843300	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 748 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 not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251302 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.