ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.1387A>C (p.Ser463Arg)

dbSNP: rs138974583
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001037614 SCV001201038 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2021-07-17 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH3-related conditions. This variant is present in population databases (rs138974583, ExAC 0.005%). This sequence change replaces serine with arginine at codon 463 of the MLH3 protein (p.Ser463Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine.
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV001270225 SCV001364356 likely pathogenic Premature ovarian failure 2020-03-02 criteria provided, single submitter research
Ambry Genetics RCV002391101 SCV002699042 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-29 criteria provided, single submitter clinical testing The p.S463R variant (also known as c.1387A>C), located in coding exon 1 of the MLH3 gene, results from an A to C substitution at nucleotide position 1387. The serine at codon 463 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003321784 SCV004027533 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing

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