Submissions for variant NM_001754.5(RUNX1):c.167T>C (p.Leu56Ser)

gnomAD frequency: 0.01206  dbSNP: rs111527738

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV000226755	SCV000965641	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2019-07-26	reviewed by expert panel	curation	The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is >/= 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBF-beta binding and sub-cellular localization (BS3; PMID: 23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP2.
Invitae	RCV000226755	SCV000287182	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891806	SCV000308031	benign	RUNX1-related disorder	2019-10-22	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Illumina Laboratory Services, Illumina	RCV000226755	SCV000435952	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000226755	SCV000743126	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2015-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000680395	SCV001753940	benign	not provided	2019-07-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31385734, 31289210, 11921279, 21343560, 27106701, 22753902, 28386644)
Sema4, Sema4	RCV002256141	SCV002535853	benign	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000680395	SCV003916330	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	RUNX1: PP3, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002277588	SCV004015357	benign	Acute myeloid leukemia	2023-07-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000226755	SCV000745582	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2015-05-08	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000680395	SCV001798345	likely benign	not provided		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000226755	SCV002515757	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		no assertion criteria provided	research
Nadeem Sheikh Lab, University of the Punjab	RCV002277588	SCV002564649	likely pathogenic	Acute myeloid leukemia		no assertion criteria provided	clinical testing