ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1724G>C (p.Arg575Thr)

gnomAD frequency: 0.00001  dbSNP: rs748185540
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001012902 SCV001173418 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-20 criteria provided, single submitter clinical testing The p.R575T variant (also known as c.1724G>C), located in coding exon 15 of the MLH1 gene, results from a G to C substitution at nucleotide position 1724. The arginine at codon 575 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001051459 SCV001215613 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-05-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 575 of the MLH1 protein (p.Arg575Thr). This variant is present in population databases (rs748185540, gnomAD 0.007%). 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. 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 not expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 819939). This variant has not been reported in the literature in individuals affected with MLH1-related conditions.
Color Diagnostics, LLC DBA Color Health RCV001012902 SCV001346231 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-21 criteria provided, single submitter clinical testing This missense variant replaces arginine with threonine at codon 575 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 hereditary cancer in the literature. This variant has been identified in 1/251222 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.

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