ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.4301A>G (p.Lys1434Arg)

gnomAD frequency: 0.00001  dbSNP: rs772866061
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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 RCV000471865 SCV000551765 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-09-25 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1434 of the MLH3 protein (p.Lys1434Arg). This variant is present in population databases (rs772866061, gnomAD 0.003%). 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: 410888). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine 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 RCV004022840 SCV002627539 uncertain significance not specified 2024-12-04 criteria provided, single submitter clinical testing The c.4301A>G (p.K1434R) alteration is located in exon 13 (coding exon 12) of the MLH3 gene. This alteration results from a A to G substitution at nucleotide position 4301, causing the lysine (K) at amino acid position 1434 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005010364 SCV005635749 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-03-19 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003899929 SCV004712999 uncertain significance MLH3-related disorder 2024-01-09 no assertion criteria provided clinical testing The MLH3 c.4301A>G variant is predicted to result in the amino acid substitution p.Lys1434Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410888/). 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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