ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.3676G>A (p.Ala1226Thr)

gnomAD frequency: 0.00003  dbSNP: rs747817741
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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 RCV001874961 SCV002142420 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2023-11-06 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 1226 of the MLH3 protein (p.Ala1226Thr). This variant is present in population databases (rs747817741, gnomAD 0.007%). 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: 1372959). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 RCV004040571 SCV002615747 uncertain significance not specified 2023-11-10 criteria provided, single submitter clinical testing The p.A1226T variant (also known as c.3676G>A), located in coding exon 6 of the MLH3 gene, results from a G to A substitution at nucleotide position 3676. The alanine at codon 1226 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002478196 SCV002782597 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2022-05-04 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003401811 SCV004120772 uncertain significance MLH3-related disorder 2023-07-05 criteria provided, single submitter clinical testing The MLH3 c.3676G>A variant is predicted to result in the amino acid substitution p.Ala1226Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-75500161-C-T). 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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