ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.958T>G (p.Cys320Gly)

gnomAD frequency: 0.00003  dbSNP: rs1334932761
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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 RCV001247345 SCV001420759 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2021-08-05 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MLH3-related conditions. This sequence change replaces cysteine with glycine at codon 320 of the MLH3 protein (p.Cys320Gly). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and glycine.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268461 SCV002551448 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002268461 SCV003999112 uncertain significance not specified 2023-04-07 criteria provided, single submitter clinical testing The p.C320G variant (also known as c.958T>G), located in coding exon 1 of the MLH3 gene, results from a T to G substitution at nucleotide position 958. The cysteine at codon 320 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Fulgent Genetics, Fulgent Genetics RCV005012683 SCV005633318 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-06-05 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003973162 SCV004794794 uncertain significance MLH3-related disorder 2024-02-05 no assertion criteria provided clinical testing The MLH3 c.958T>G variant is predicted to result in the amino acid substitution p.Cys320Gly. This variant was reported in an individual with melanoma (Ticha et al. 2019. PubMed ID: 31745173). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/971541/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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