ClinVar Genomic variation as it relates to human health

Variant summary: MLH1 c.52C>T (p.Arg18Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.52C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome/Pediatric cancer cohort (example, Taylor_2003, Hardt_2011, Yurgelun_2015, Chubb_2015, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

The frequency of this variant in the general population, 0.00007 (8/113708 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 14635101 (2003), 25559809 (2015)), a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015), 21404117 (2011)), pediatric cancer (PMID: 26580448 (2015)), uveal melanoma (PMID: 29625052 (2018)), and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). It has also been reported in unaffected individuals (PMID: 24728327 (2014), PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.52C>T, in exon 1 that results in an amino acid change, p.Arg18Cys. This sequence change has been reported in a patient with early onset proximal colorectal cancer with microsatellite instability and a family history of CRC in a sibling (PMID: 25559809). It has also been reported in few other patients with colorectal cancer but no additional patient specific clinical information was provided (PMIDs: 25980754, 21404117, and 14635101). This sequence change has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs367654552). The p.Arg18Cys change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. The p.Arg18Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg18Cys change remains unknown at this time.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 18 of the MLH1 protein (p.Arg18Cys). This variant is present in population databases (rs367654552, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma, acute lymphocytic leukemia and/or clinical features of Lynch syndrome (PMID: 14635101, 21404117, 22144684, 25980754, 26580448, 29625052). ClinVar contains an entry for this variant (Variation ID: 134656). 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) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. 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.

This missense variant replaces arginine with cysteine at codon 18 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 individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 14635101, 21404117, 25559809, 25980754) or breast cancer (PMID: 32601921), and has also been in a healthy control (PMID: 24728327). This variant has been identified in 8/251420 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.

This missense variant replaces arginine with cysteine at codon 18 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 individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 14635101, 21404117, 25559809, 25980754) or breast cancer (PMID: 32601921), and has also been in a healthy control (PMID: 24728327). This variant has been identified in 8/251420 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.

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.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals suspected of having Lynch syndrome, including at least one individual whose tumor showed microsatellite instability (PMID: 21404117, 14635101, 25559809, 25980754); This variant is associated with the following publications: (PMID: 24728327, 14635101, 22949387, 21404117, 25980754, 25559809, 26296696, 32008151, 29625052, 26580448, 36451132, 32601921, 33471991, 35980532, 22753075)

MLH1: PP3

The MLH1 c.52C>T variant is predicted to result in the amino acid substitution p.Arg18Cys. This variant has been reported in at least five individuals with either suspected Lynch syndrome or a personal and family history of colorectal cancer (Taylor et al. 2003. PubMed ID: 14635101; Hardt et al. 2011. PubMed ID: 21404117; Chubb et al. 2015. PubMed ID: 25559809; Yurgelun et al. 2015. PubMed ID: 25980754). It has also been reported in two individuals with acute lymphoblastic leukemia (Zhang et al. 2015. PubMed ID: 26580448) and one individual with uveal melanoma (Huang et al. 2018. PubMed ID: 29625052). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance by the vast majority of sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134656/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.