ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.3689G>A (p.Arg1230His)

gnomAD frequency: 0.00001  dbSNP: rs781739661
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001121762 SCV001280409 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001121762 SCV001417600 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1230 of the MLH3 protein (p.Arg1230His). This variant is present in population databases (rs781739661, gnomAD 0.03%). 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: 888447). 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 RCV002451329 SCV002613721 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-02 criteria provided, single submitter clinical testing The p.R1230H variant (also known as c.3689G>A), located in coding exon 6 of the MLH3 gene, results from a G to A substitution at nucleotide position 3689. The arginine at codon 1230 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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.

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