ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.160G>A (p.Gly54Arg)

gnomAD frequency: 0.00001  dbSNP: rs1315572872
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773535 SCV000907229 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001232048 SCV001404592 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-03-23 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). 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. ClinVar contains an entry for this variant (Variation ID: 628871). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 54 of the MLH1 protein (p.Gly54Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions.
Baylor Genetics RCV004569446 SCV005058004 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2024-01-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773535 SCV005134158 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-29 criteria provided, single submitter clinical testing The p.G54R variant (also known as c.160G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 160. The glycine at codon 54 is replaced by arginine, an amino acid with dissimilar properties. Functional studies suggest that this variant is associated with decreased mismatch repair activity; however, additional evidence is needed (Ellison AR et al. Nucleic Acids Res, 2004 Oct;32:5321-38). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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