Submissions for variant NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser)

gnomAD frequency: 0.00003  dbSNP: rs370315332

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV002264713	SCV002546390	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2022-07-08	reviewed by expert panel	curation	The NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser) variant is reported at a frequency of 0.00004476 (0.004%, 5/111718 alleles) in the non-Finnish European population of gnomAD v2.1.1 cohort which does not fall within 0.00015 (0.015%) and 0.0015 (0.15%) range, thus not meeting BS1 criteria. 1 patient from PMID: 24764152 with chronic myelomonocytic leukemia is reported with the Pro263Ser variant at a VAF of 49%. Patient also had variants in SETBP1 and U2AF1. However, information on germ line confirmation is not available. Proband does not meet criteria for PS4. This missense variant has a REVEL score 0.286, which does not meet criteria for PP3 or BP4. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: none.
Invitae	RCV000528679	SCV000638158	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the RUNX1 protein (p.Pro263Ser). This variant is present in population databases (rs370315332, gnomAD 0.004%). 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: 464008). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765504	SCV000896807	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1; Acute myeloid leukemia	2022-05-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003129891	SCV003814340	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470746	SCV004209845	uncertain significance	Acute myeloid leukemia	2023-09-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000528679	SCV004806570	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-03-26	criteria provided, single submitter	clinical testing