Table 1.
Prioritized germline HL candidates
| Family | Sample count | Affected plus obligate carriers | Early-onset family | Within 1-LOD MLOD region | ACMG evidence | Pathogenicity | Priority | Gene | Type | HGVS |
|---|---|---|---|---|---|---|---|---|---|---|
| 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.