ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.1306A>G (p.Asn436Asp)

gnomAD frequency: 0.00001  dbSNP: rs754824568
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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 RCV001366710 SCV001563023 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 436 of the MLH3 protein (p.Asn436Asp). This variant is present in population databases (rs754824568, gnomAD 0.02%). 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: 1057680). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The aspartic acid 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 RCV004036982 SCV002691343 likely benign not specified 2024-05-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV004036982 SCV005090116 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005005211 SCV005633312 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-02-04 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003908551 SCV004721735 uncertain significance MLH3-related disorder 2023-11-17 no assertion criteria provided clinical testing The MLH3 c.1306A>G variant is predicted to result in the amino acid substitution p.Asn436Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-75515053-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1057680/). 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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