ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.739T>G (p.Ser247Ala)

gnomAD frequency: 0.00001  dbSNP: rs63750948
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629785 SCV000750741 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV001026384 SCV001188754 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-28 criteria provided, single submitter clinical testing The p.S247A variant (also known as c.739T>G), located in coding exon 9 of the MLH1 gene, results from a T to G substitution at nucleotide position 739. The serine at codon 247 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320096 SCV004024340 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001026384 SCV004359201 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-09 criteria provided, single submitter clinical testing This missense variant replaces serine with alanine at codon 247 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 9/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.739T>C (p.Ser247Pro), is considered to be disease-causing (ClinVar variation ID: 126985), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV003997209 SCV004836921 uncertain significance Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces serine with alanine at codon 247 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 9/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.739T>C (p.Ser247Pro), is considered to be disease-causing (ClinVar variation ID: 126985), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Harris Lab, University of Minnesota RCV000114847 SCV000148742 not provided not provided no assertion provided not provided

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