ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.2819C>T (p.Ser940Phe)

gnomAD frequency: 0.00002  dbSNP: rs746725349
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001053000 SCV001217241 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2023-02-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 940 of the MLH3 protein (p.Ser940Phe). This variant is present in population databases (rs746725349, gnomAD 0.04%), 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: 849112). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The phenylalanine 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 RCV004031664 SCV002746634 uncertain significance not specified 2023-09-14 criteria provided, single submitter clinical testing The p.S940F variant (also known as c.2819C>T), located in coding exon 1 of the MLH3 gene, results from a C to T substitution at nucleotide position 2819. The serine at codon 940 is replaced by phenylalanine, an amino acid with highly 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153910 SCV003843770 likely pathogenic Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing

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