ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1196G>A (p.Ser399Asn)

dbSNP: rs946348885
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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 RCV004692289 SCV005196492 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-07-17 reviewed by expert panel curation NM_001754.5(RUNX1):c.1196G>A (p.Ser399Asn) is a missense variant with a REVEL score <0.50 (0.053) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (MPN/MDS) (PMID: 32241844) (PS4_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001239228 SCV001412083 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-11-03 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 399 of the RUNX1 protein (p.Ser399Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 964908). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. 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.

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