Submissions for variant NM_001754.5(RUNX1):c.973C>T (p.Pro325Ser)

gnomAD frequency: 0.00001  dbSNP: rs746531841

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004693322	SCV005196547	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-07-25	reviewed by expert panel	curation	NM_001754.4(RUNX1):c.973C>T (p.Pro325Ser) is a missense variant which is absent from gnomAD v2, but has a highest population minor allele frequency of 0.006543% (1/15284 alleles) in the African American/African population from gnomAD v3. This variant is not published, and out of 19 carriers reported in clinical laboratories, only one was diagnosed with MDS in their 40s and is a confirmed germline carrier (PS4_supporting). The computational predictor REVEL gives a score of 0.05, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (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: PS4_supporting and BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806840	SCV000946859	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-07-08	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 325 of the RUNX1 protein (p.Pro325Ser). This variant is not present in population databases (gnomAD no frequency). 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: 651472). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Baylor Genetics	RCV003467417	SCV004209860	uncertain significance	Acute myeloid leukemia	2023-08-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004958121	SCV005495379	uncertain significance	Inborn genetic diseases	2024-11-20	criteria provided, single submitter	clinical testing	The c.973C>T (p.P325S) alteration is located in exon 9 (coding exon 8) of the RUNX1 gene. This alteration results from a C to T substitution at nucleotide position 973, causing the proline (P) at amino acid position 325 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.