ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.788A>G (p.Asn263Ser)

gnomAD frequency: 0.00001  dbSNP: rs104894997
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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 RCV000526305 SCV000625194 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-12-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 263 of the MLH1 protein (p.Asn263Ser). This variant is present in population databases (rs104894997, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 455454). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV000563114 SCV000662119 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-06 criteria provided, single submitter clinical testing The p.N263S variant (also known as c.788A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 788. The asparagine at codon 263 is replaced by serine, 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.
Color Diagnostics, LLC DBA Color Health RCV000563114 SCV000908613 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV003470710 SCV004192969 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-13 criteria provided, single submitter clinical testing

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