Page 74 - Haematologica Vol. 109 - July 2024

ARTICLE - Familial germline pathogenic alleles and hematologic malignancies Q. Feng et al.
Ancestry of pathogenic/likely pathogenic germline variants
For the one LAT family with a shared sibling variant, the P/LP variant in ATM was shared on an SAS haplotype. For NLW families, the P/LP variants on TP53 and NOD2 shared EUR ancestry, which match their predicted dominant global ancestry. For one NLB family, the P/LP variant on GATA2 shared AFR ancestry on local haplotypes and this
matches their predicted dominant global ancestry. For NLAPI families, 2 pathogenic variants were classified as AMR and one (the novel HABP2 variant) as EAS. For the one NLAIAN family, the P/LP variant on SBF2 has shared local EUR ancestry, which matched their predicted dom- inant global ancestry (Figure 1, Online Supplementary Table S3).
Figure 1. Predicted global ancestries of study subjects and local ancestries of putatively pathogenic variants, California Cancer Registry, 1989-2015. *Predicted local ancestry matches the predicted dominant global ancestry. LW: Latino White; NLW: non-Lati- no White; NLB: non-Latino Black; NLAPI: non-Latino Asian/Pacific Islander; NLAIAN: non-Latino American Indian/Alaskan Native; AFR: African; AMR: Admixed American; EAS: East Asian; SAS: South Asian; EUR: European.
Table 2. Distribution of rare variants shared by two siblings in a family, California Cancer Registry, 1989-2015.
Pathogenic variants N=9
VUS N=105
Overall mutations N=113
N. of families N=32
VUS per family
Self-reported race/ethnicity, N (%) Latino, all races
NLW
NLB
NLAPI NLAIAN
1 (11) 2 (22) 2 (22) 2 (22) 1 (11)
41 (39) 21 (22) 10 (10) 27 (28) 1 (1)
44 (39) 24 (21) 12 (11) 31 (27) 2 (2)
12 (38) 10 (31) 3 (9) 6 (19) 1 (3)
3.2 2.2 3.3 4.7 1.0
Category, N (%) Cancer Hematologic Immunologic Other
6 (73) 1 (7) 1 (13) 0 (0)
79 (68) 10 (11) 9 (9) 2 (2)
78 (69.0) 12 (10.6) 11 (9.7) 1 (0.9)
28 (58) 11 (23) 8 (17) 1 (2)
2.4 1.0 1.1 1.0
Mutation class, N (%) Frameshift Missense Nonsense
Protein deletion Splice
6 (67) -
3 (33)
-
105-(97) 0 (0)
2 (2)
-
6 (5) 101 (89) 3 (3)
2 (2)
1 (1)
6 (14) 30 (71) 3 (7) 2 (5) 1 (2)
0.0 3.2 0.3 1.0 0.0
VUS: variants of uncertain significance; NLW: non-Latino White; NLB: non-Latino Black; NLAPI: non-Latino Asian/Pacific Islander; NLAIAN: non-Latino American Indian/Alaskan Native.
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