ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.35C>G (p.Ser12Trp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004775438 SCV005382754 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-10-29 reviewed by expert panel curation NM_001754.5(RUNX1):c.35C>G (p.Ser12Trp) is a missense variant which is absent from gnomAD v2, v3, and v4.1 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.631, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV003515066 SCV004318663 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-08-20 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the RUNX1 protein (p.Ser12Trp).

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