Variant: NM_001754.4(RUNX1):c.973C>T (p.Pro325Ser)

CA10014230

651472 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: be94fc5f-d697-4b41-92ca-de27c51dcf76

Approved on: 2024-07-25

Published on: 2024-07-25

HGVS expressions

NM_001754.4:c.973C>T
NM_001754.4(RUNX1):c.973C>T (p.Pro325Ser)
NC_000021.9:g.34792605G>A
CM000683.2:g.34792605G>A
NC_000021.8:g.36164902G>A
CM000683.1:g.36164902G>A
NC_000021.7:g.35086772G>A
NG_011402.2:g.1197107C>T
ENST00000675419.1:c.973C>T
ENST00000300305.7:c.973C>T
ENST00000344691.8:c.892C>T
ENST00000399240.5:c.700C>T
ENST00000437180.5:c.973C>T
ENST00000482318.5:c.*563C>T
NM_001001890.2:c.892C>T
NM_001001890.3:c.892C>T
NM_001754.5:c.973C>T

Uncertain Significance

• Met criteria codes: BP4 PS4_Supporting

• Not Met criteria codes: PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5 BP7 PS2 PS3 PS1 PM6 PM2 PM3 PM1 PM4 PM5 BA1 PP4 PP1 PP3 PP2

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Myeloid Malignancy VCEP

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.

Met criteria codes

• BP4: REVEL score = 0.05, which is lower than the v2 threshold of 0.50. No splicing impact predicted by SpliceAI (Δ scores ≤ 0.20).
• PS4_Supporting: The variant has not been published in the literature or databases, but has been identified in the germline (unaffected child is also a carrier) of a patient who developed MDS in their 40s. It has also been reported in clinical laboratories in patients with unrelated cancer diagnoses or where germline origin could not be confirmed (one patient being evaluated for SCID/CID/Cytopenias).

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: Not applicable
• BS4: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• BS3: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• BS1: gnomAD v2: absent from database with a mean coverage of at least 20x gnomAD v3: ALL: 0.0006573% (1/152134 alleles) - AMR: 0.006543% (1/15284 alleles)
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: Not applicable
• BP1: Not applicable
• BP5: Not applicable
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• PS3: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• PS1: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• PM6: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• PM2: gnomAD v2: absent from database with a mean coverage of at least 20x gnomAD v3: ALL: 0.0006573% (1/152134 alleles) - AMR: 0.006543% (1/15284 alleles)
• PM3: Not applicable
• PM1: The variant is not present at a hotspot or in the critical region of the runt homology domain.
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: Other variants at P325 or P298 were not found in HGMD, COSMIC, or Mastermind.
• BA1: gnomAD v2: absent from database with a mean coverage of at least 20x gnomAD v3: ALL: 0.0006573% (1/152134 alleles) - AMR: 0.006543% (1/15284 alleles)
• PP4: Not applicable
• PP1: The variant has not been reported in the literature, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar.
• PP3: REVEL score = 0.05, which is not higher than the v2 threshold of 0.88.
• PP2: Not applicable