ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.4268G>A (p.Arg1423His)

gnomAD frequency: 0.00007  dbSNP: rs752635498
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001059150 SCV001223762 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1423 of the MLH3 protein (p.Arg1423His). This variant is present in population databases (rs752635498, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 854166). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics RCV004031869 SCV002631555 uncertain significance not specified 2024-11-24 criteria provided, single submitter clinical testing The p.R1423H variant (also known as c.4268G>A), located in coding exon 12 of the MLH3 gene, results from a G to A substitution at nucleotide position 4268. The arginine at codon 1423 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is 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.
PreventionGenetics, part of Exact Sciences RCV003405269 SCV004113250 uncertain significance MLH3-related disorder 2023-01-13 criteria provided, single submitter clinical testing The MLH3 c.4268G>A variant is predicted to result in the amino acid substitution p.Arg1423His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-75483879-C-T). It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/854166). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV004031869 SCV005090099 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005012506 SCV005635751 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-02-01 criteria provided, single submitter clinical testing

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