Submissions for variant NM_001754.5(RUNX1):c.952T>G (p.Ser318Ala)

gnomAD frequency: 0.00013  dbSNP: rs545554349

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV001290709	SCV001478846	benign	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2021-01-11	reviewed by expert panel	curation	This missense variant is present in gnomAD (v2) at an allele frequency 0.6377% >0.15% with 226 out of 35438 alleles in Latino subpopulation (BA1). Additionally, this missense variant has a REVEL score <0.15 (0.093), and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4.
Invitae	RCV000456819	SCV000560765	benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-01-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256310	SCV002535881	likely benign	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227764	SCV003924144	likely benign	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1; Acute myeloid leukemia	2021-03-30	criteria provided, single submitter	clinical testing	RUNX1 NM_00175.4 exon 8 p.Ser318Ala (c.952T>G): This variant has been reported in the literature in one individual with acute myeloid leukemia and in another individual and his cousin who both had neutropenia and CHDs. However, both of these family members also carried additional pathogenic variants in G6PC3 that could explain their phenotypes (Mendler 2013 PMID: 23753029, Stray-Pedersen 2016 PMID:27577878). However, this variant is also present in 0.1% (17/15284) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/21-34799316-A-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:415833). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign
PreventionGenetics, part of Exact Sciences	RCV003932752	SCV004747928	likely benign	RUNX1-related disorder	2021-12-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).