ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.1669G>A (p.Ala557Thr)

gnomAD frequency: 0.00001  dbSNP: rs1347649293
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000694910 SCV000823376 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 557 of the MLH3 protein (p.Ala557Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 573276). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine 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 RCV004025223 SCV002708488 uncertain significance not specified 2023-05-05 criteria provided, single submitter clinical testing The p.A557T variant (also known as c.1669G>A), located in coding exon 1 of the MLH3 gene, results from a G to A substitution at nucleotide position 1669. The alanine at codon 557 is replaced by threonine, an amino acid with similar 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.
PreventionGenetics, part of Exact Sciences RCV003411617 SCV004113922 uncertain significance MLH3-related disorder 2023-02-24 criteria provided, single submitter clinical testing The MLH3 c.1669G>A variant is predicted to result in the amino acid substitution p.Ala557Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~251,000 alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-75514690-C-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/573276/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics RCV005010696 SCV005635795 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-01-26 criteria provided, single submitter clinical testing

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