Page 35 - Haematologica April 2020

RUNX1 variant curation
fibroblasts later confirmed the germline, nonsense RUNX1 variant. Her two sons and granddaughter also tested positive for the RUNX1 variant (Figure 1).
Similar to this case, most patients with FPD/AML will have a characteristic phenotype (Table 1) including mild to moderate thrombocytopenia with normal platelet size, platelet α or dense granule secretion defects and impaired
platelet aggregation, particularly in response to collagen and epinephrine as well as a predisposition to hematolog- ic malignancies. Although there is variability in disease onset in FPD/AML,3 development of a hematologic malig- nancy is common with a lifetime risk of ~44%: AML and MDS are common, other malignancies occur less fre- quently (Table 1).19-23 FPD/AML has a high but incomplete
Table 3. Summary of RUNX1 variant examples with application of the Myeloid Malignancy Variant Curation Expert Panel criteria.
Example No.
1
2
3
4
5 6
RUNX1 variant NM_001754 (isoform C)
c.610C>T (p.Arg204Ter)
c.314A>C p.(His105Pro)
c.315C>A p.(His105Gln) c.253C>A p.(His85Asn)
c.508+3delA c.444C>T p.(Thr148=)
c.1257G>A p.(Val419=)
Copy number variant, deletion of exon 2
c.1118C>A (p.Ser373Ter)
ClinVar Assertion
PATH
VUS
CONF: OMIM: PATH Invitae: VUS
PATH Illumina: VUS Invitae: LBEN VUS
Criteria MM-VCEP classification
PVS1, PM2, PS4_supporting, PP1 PATH
PM2, PP3, PS4_supporting, PM1_supporting, PM5_supporting LPATH
PS3, PM2, PP3, PM1_supporting LPATH BS1, BS3, PP3 LBEN
PS3, PP1_strong, PM2, PP3, PS4_supporting PATH BP4, BP7 LBEN
VUS PS4, PP1_strong, PM2, PVS1_moderate PATH
PVS1_strong, PM2, PS4_supporting LPATH
The five-tier ClinVar classification: PATH (pathogenic), LPATH (likely pathogenic),VUS (variant of uncertain significance), LBEN (likely benign), BEN (benign); CONF (conflict- ing interpretations in ClinVar); criteria from Luo and Feurstein et al.18
Figure 1. Family pedigree of a patient with acute myeloid leukemia, example 1. Germline RUNX1 NM_001754:c.610C>T, (p.Arg204Ter) showing typical autosomal dominant inheritance with other first and sec- ond-degree relatives with thrombocytopenia and/or myeloid malignancy (acute myeloid leukemia and myelodysplastic syndrome). mut: mutated; MDS: myelodysplastic syn- drome; sAML: secondary acute myeloid leukemia; +: wildtype.
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