Table 1.

Prioritized germline HL candidates

FamilySample countAffected plus obligate carriersEarly-onset familyWithin 1-LOD MLOD regionACMG evidencePathogenicityPriorityGeneTypeHGVS
HL1000001 4 2   PVS1∗, PP1∗ LP∗, VUS C3 MST1R Coding NM_002447.4:c.697delinsCA (p.V233Cfs∗16) 
HL1000003 4 2   PM2_supporting, PP1_moderate∗, PP3 VUS, VUS∗ NC1 PAX5 Noncoding NM_016734.3:c.605-2310C>T 
HL1000007 4 2   PVS1∗, PP1∗ LP∗, VUS C3 GPNMB Coding NM_002510.3:c.367+2T>C 
HL1000007 4 2   PVS1∗, PP1∗ LP∗, VUS C3 BLK Coding NM_001715.3:c.369-2A>G 
HL1000056 4 3   BP4, PP1∗ VUS∗, VUS C2 REL Coding NM_001291746.2:c.920A>G (p.H307R) 
HL1000059 4 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 IGSF10 Coding NM_178822.5:c.3296C>G (p.S1099∗) 
HL1000059 4 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 GSN Coding NM_198252.3:c.1662G>A (p.W554∗) 
HL1000060 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 CARD9 Coding NM_052813.5:c.184+1G>A 
HL1000060 4 2   BP4, PP1∗ VUS∗, VUS C3 MROH2A Coding NM_001394639.1:c.4452+1G>A 
HL1000060 4 2   PVS1∗, PP1∗ LP∗, VUS C3 ACOT8 Coding NM_005469.4:c.488+1G>A 
HL1000060 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 ZNF683 Coding NM_001114759.3:c.103C>T (p.R35∗) 
HL1000063 3 2   PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL1000064 5 2   PVS1_moderate, PM2_supporting, PP1 VUS C1 KDR∗ Coding NM_002253.4:c.3849-2A>C 
HL1000064 5 2   PP1∗, PP3 VUS∗, VUS NC1 RUNX3 Noncoding NM_004350.3:c.-61138C>T 
HL1000065 7 3   PP1∗, PP3 VUS∗, VUS NC1 MYB Noncoding NM_001130173.2:c.-4939del 
HL1000065 7 3   PP1∗, PP3 VUS∗, VUS NC1 ATF3 Noncoding NM_001674.4:c.-5+978A>C 
HL1000078 5 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 POLR1E Coding NM_022490.4:c.847del (p.L283Sfs∗9) 
HL1000078 5 2   PM2_supporting, PP1∗, BP4 VUS∗, VUS C1 JUNB Coding NM_002229.3:c.334C>T (p.P112S) 
HL16594 6 2 X  BP4, PP1∗ VUS∗, VUS C1 TCF3 Coding NM_003200.5:c.1486G>A (p.E496K) 
HL16594 6 2 X  BP4, PP1∗ VUS∗, VUS C2 HBS1L Coding NM_006620.4:c.1162A>G (p.I388V) 
HL213 6 2 X  PM2_supporting, PP1∗, BP4 VUS∗, VUS C1 RAD51D Coding NM_002878.4:c.911G>A (p.G304D) 
HL2350 6 4  X PS3_supporting, PP1_strong∗ VUS∗, VUS C1 KDR∗ Coding NM_002253.4:c.3193G>A (p.A1065T) 
HL2408 4 2   PM2_supporting, PP1∗, PP3 VUS∗, VUS C3 CDT1 Coding NM_030928.4::c.1477+3_1477+24del () 
HL2408 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 POLR1E Coding NM_022490.4:c.445C>T (p.R149∗) 
HL2491 6 2   PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL2491 6 2   PP1∗, PP3 VUS∗, VUS NC1 GATA3 Noncoding NM_001002295.2:c.779-2563G>A 
HL2694 11 4  X PVS1∗, PM2_supporting, PP1_moderate∗ P∗, VUS C3 EEF2KMT Coding NM_201400.4:c.529A>T (p.K177∗) 
HL2696 5 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 EFR3B Coding NM_014971.2:c.853C>T (p.Q285∗) 
HL3262 7 3   PM2_supporting, PP1∗, PP3 VUS∗, VUS C3 EIF1AD Coding NM_001242481.2:c.88-4C>G 
HL3262 7 3   PS3_supporting, PP1_strong∗ VUS∗, VUS C1 KDR∗ Coding NM_002253.4:c.3193G>A (p.A1065T) 
HL3262 7 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 DDX10 Coding NM_004398.4:c.2059A>T (p.K687∗) 
HL3350 9 2 X  PM2_supporting, PP1∗, PP2 VUS∗, VUS C1 STAT3 Coding NM_139276.3:c.849A>T (p.K283N) 
HL3402 8 4  X PVS1∗, PM2_supporting, PP1_moderate∗ P∗, VUS C1 IRF7 Coding NM_001572.5:c.396G>A (p.W132∗) 
HL3929 3 3   PP1∗, PP3 VUS∗, VUS NC1 GATA3 Noncoding NM_001002295.2:c.779-2563G>A 
HL3929 3 3   PS3_supporting, PP1_moderate, PP3 VUS∗, VUS C1 POT1∗ Coding NM_015450.3:c.670G>A (p.D224N) 
HL4450 7 5  X PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL4479 7 2   BP4, PP1∗ VUS∗, VUS C1 BAD Coding NM_032989.3:c.397A>C (p.K133Q) 
HL4479 7 2   BP4, PP1∗ VUS∗, VUS C1 CLEC16A Coding NM_015226.3:c.2578C>T (p.R860C) 
HL4643 18 5   PP1∗, PP3 VUS∗, VUS NC1 IRF8 Noncoding NM_002163.4:c.-1-1639C>T 
HL5171 5 2   PP1∗ VUS∗, VUS C2 MET Coding NM_000245.4:c.2318C>T (p.P773L) 
HL5171 5 2   BP4, PP1∗ VUS∗, VUS C1 MAP3K7 Coding NM_145331.3:c.1282G>A (p.V428I) 
HL533 6 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 ARMC9 Coding NM_001352754.2:c.1268_1271del (p.K423Rfs∗29) 
HL6898 7 3  X PM2_supporting, PP1_moderate∗, PP3 VUS, VUS∗ NC1 PAX5 Noncoding NM_016734.3:c.605-2310C>T 
HL696 7 2 X  PVS1∗, PP1_moderate∗ P∗, VUS C3 TPRG1 Coding NM_198485.4:c.183_192del (p.Y61∗) 
FamilySample countAffected plus obligate carriersEarly-onset familyWithin 1-LOD MLOD regionACMG evidencePathogenicityPriorityGeneTypeHGVS
HL1000001 4 2   PVS1∗, PP1∗ LP∗, VUS C3 MST1R Coding NM_002447.4:c.697delinsCA (p.V233Cfs∗16) 
HL1000003 4 2   PM2_supporting, PP1_moderate∗, PP3 VUS, VUS∗ NC1 PAX5 Noncoding NM_016734.3:c.605-2310C>T 
HL1000007 4 2   PVS1∗, PP1∗ LP∗, VUS C3 GPNMB Coding NM_002510.3:c.367+2T>C 
HL1000007 4 2   PVS1∗, PP1∗ LP∗, VUS C3 BLK Coding NM_001715.3:c.369-2A>G 
HL1000056 4 3   BP4, PP1∗ VUS∗, VUS C2 REL Coding NM_001291746.2:c.920A>G (p.H307R) 
HL1000059 4 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 IGSF10 Coding NM_178822.5:c.3296C>G (p.S1099∗) 
HL1000059 4 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 GSN Coding NM_198252.3:c.1662G>A (p.W554∗) 
HL1000060 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 CARD9 Coding NM_052813.5:c.184+1G>A 
HL1000060 4 2   BP4, PP1∗ VUS∗, VUS C3 MROH2A Coding NM_001394639.1:c.4452+1G>A 
HL1000060 4 2   PVS1∗, PP1∗ LP∗, VUS C3 ACOT8 Coding NM_005469.4:c.488+1G>A 
HL1000060 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 ZNF683 Coding NM_001114759.3:c.103C>T (p.R35∗) 
HL1000063 3 2   PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL1000064 5 2   PVS1_moderate, PM2_supporting, PP1 VUS C1 KDR∗ Coding NM_002253.4:c.3849-2A>C 
HL1000064 5 2   PP1∗, PP3 VUS∗, VUS NC1 RUNX3 Noncoding NM_004350.3:c.-61138C>T 
HL1000065 7 3   PP1∗, PP3 VUS∗, VUS NC1 MYB Noncoding NM_001130173.2:c.-4939del 
HL1000065 7 3   PP1∗, PP3 VUS∗, VUS NC1 ATF3 Noncoding NM_001674.4:c.-5+978A>C 
HL1000078 5 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 POLR1E Coding NM_022490.4:c.847del (p.L283Sfs∗9) 
HL1000078 5 2   PM2_supporting, PP1∗, BP4 VUS∗, VUS C1 JUNB Coding NM_002229.3:c.334C>T (p.P112S) 
HL16594 6 2 X  BP4, PP1∗ VUS∗, VUS C1 TCF3 Coding NM_003200.5:c.1486G>A (p.E496K) 
HL16594 6 2 X  BP4, PP1∗ VUS∗, VUS C2 HBS1L Coding NM_006620.4:c.1162A>G (p.I388V) 
HL213 6 2 X  PM2_supporting, PP1∗, BP4 VUS∗, VUS C1 RAD51D Coding NM_002878.4:c.911G>A (p.G304D) 
HL2350 6 4  X PS3_supporting, PP1_strong∗ VUS∗, VUS C1 KDR∗ Coding NM_002253.4:c.3193G>A (p.A1065T) 
HL2408 4 2   PM2_supporting, PP1∗, PP3 VUS∗, VUS C3 CDT1 Coding NM_030928.4::c.1477+3_1477+24del () 
HL2408 4 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 POLR1E Coding NM_022490.4:c.445C>T (p.R149∗) 
HL2491 6 2   PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL2491 6 2   PP1∗, PP3 VUS∗, VUS NC1 GATA3 Noncoding NM_001002295.2:c.779-2563G>A 
HL2694 11 4  X PVS1∗, PM2_supporting, PP1_moderate∗ P∗, VUS C3 EEF2KMT Coding NM_201400.4:c.529A>T (p.K177∗) 
HL2696 5 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 EFR3B Coding NM_014971.2:c.853C>T (p.Q285∗) 
HL3262 7 3   PM2_supporting, PP1∗, PP3 VUS∗, VUS C3 EIF1AD Coding NM_001242481.2:c.88-4C>G 
HL3262 7 3   PS3_supporting, PP1_strong∗ VUS∗, VUS C1 KDR∗ Coding NM_002253.4:c.3193G>A (p.A1065T) 
HL3262 7 3   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 DDX10 Coding NM_004398.4:c.2059A>T (p.K687∗) 
HL3350 9 2 X  PM2_supporting, PP1∗, PP2 VUS∗, VUS C1 STAT3 Coding NM_139276.3:c.849A>T (p.K283N) 
HL3402 8 4  X PVS1∗, PM2_supporting, PP1_moderate∗ P∗, VUS C1 IRF7 Coding NM_001572.5:c.396G>A (p.W132∗) 
HL3929 3 3   PP1∗, PP3 VUS∗, VUS NC1 GATA3 Noncoding NM_001002295.2:c.779-2563G>A 
HL3929 3 3   PS3_supporting, PP1_moderate, PP3 VUS∗, VUS C1 POT1∗ Coding NM_015450.3:c.670G>A (p.D224N) 
HL4450 7 5  X PS3_supporting, PP1_strong∗, PP3 LP∗, VUS NC1 KLHDC8B∗ Noncoding NM_173546.3:c.-158C>T 
HL4479 7 2   BP4, PP1∗ VUS∗, VUS C1 BAD Coding NM_032989.3:c.397A>C (p.K133Q) 
HL4479 7 2   BP4, PP1∗ VUS∗, VUS C1 CLEC16A Coding NM_015226.3:c.2578C>T (p.R860C) 
HL4643 18 5   PP1∗, PP3 VUS∗, VUS NC1 IRF8 Noncoding NM_002163.4:c.-1-1639C>T 
HL5171 5 2   PP1∗ VUS∗, VUS C2 MET Coding NM_000245.4:c.2318C>T (p.P773L) 
HL5171 5 2   BP4, PP1∗ VUS∗, VUS C1 MAP3K7 Coding NM_145331.3:c.1282G>A (p.V428I) 
HL533 6 2   PVS1∗, PM2_supporting, PP1∗ P∗, VUS C3 ARMC9 Coding NM_001352754.2:c.1268_1271del (p.K423Rfs∗29) 
HL6898 7 3  X PM2_supporting, PP1_moderate∗, PP3 VUS, VUS∗ NC1 PAX5 Noncoding NM_016734.3:c.605-2310C>T 
HL696 7 2 X  PVS1∗, PP1_moderate∗ P∗, VUS C3 TPRG1 Coding NM_198485.4:c.183_192del (p.Y61∗) 

Prioritized variants for each family based on segregation and predicted deleteriousness. Family specific information including sample count and number of affected and obligate carriers and counts for each priority level are provided in addition to highlighted variant details. Variants in KLHDC8B NM_173546.3:c.-158C>T, KDR NM_002253.4:c.3849-2A>C, and POT1 were previously reported based on WES analysis of the same NCI pedigrees.16,17,21 

BP, benign supporting; HGVS, Human Genome Variation Society; LP, likely pathogenic; P, pathogenic; PM, pathogenic moderate; PP, pathogenic supporting; PS, pathogenic strong; PVS, pathogenic very strong; VUS, variant of unknown significance.

∗Where evidence applied based on hypothesis of genotype-phenotype correlation.

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