ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.2327A>T (p.Asn776Ile)

gnomAD frequency: 0.00014  dbSNP: rs150742442
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000815684 SCV000956148 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 776 of the MLH3 protein (p.Asn776Ile). This variant is present in population databases (rs150742442, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. 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: 658796). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine 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 RCV004028863 SCV002732924 uncertain significance not specified 2024-09-25 criteria provided, single submitter clinical testing The p.N776I variant (also known as c.2327A>T), located in coding exon 1 of the MLH3 gene, results from an A to T substitution at nucleotide position 2327. The asparagine at codon 776 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV005012360 SCV005635786 uncertain significance Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer 2024-01-07 criteria provided, single submitter clinical testing

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