Rare heterozygous ERG variants and population variants
| Patient no. . | Sex . | ERG variant (479 aa) . | VAF (%) . | gnomAD v4.0.0 . | REVEL . | Hematological-related phenotype . | Nonhematological phenotype . | Age onset of first phenotype (y) . | Germ line ERG (inherited/de novo) (Sample) . | Somatic variants . | Chr 21q cnLOH . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | E20Vfs∗13 | 60 | 0 | NA | MDS | 38 | Yes (MSC) | No | ||
| 2 | F | P116R | 56 | 69 0.004% | 0.36 | Thrombocytopenia, thrombocytopathy, and platelet aggregation disorder | Hypertension, diabetes, cataract | 73 | No | ||
| 3 | V127Efs∗82 | 50 | 0 | NA | ALL | <18 | Yes | ||||
| 4 | I126T | 59 | 1 0.00016% | 0.512 | Chronic thrombocytopenia | Not reported in clinical records | <14 | Yes (SF) | FLT3-ITD and IDH1 | ||
| AML | 40 | ||||||||||
| 5 | M | R302C | 40 | 10 0.00068% (1× R302L) (17× R302H) | 0.365 | CLL | Not reported in clinical records | Unknown | Yes (hair) | ||
| 6 | F | P306L | 44 | 0 (6× P306W) | 0.394 | None | Lymphedema | <1 | Yes (inherited) (PB) | No | |
| 7 | M | P306L | 57 | 0 (6× P306W) | 0.394 | None | Lymphedema | Yes | |||
| 8 | F | M341V | 45 | 0 | 0.45 | Severe congenital aplasia and abnormal B cells | Prematurity for acute fetal distress (33 wk) | 0 | Yes (inherited) (SF) | None | |
| 9 | F | M341V | 45 | 0 | 0.45 | MDS | 56 | No | |||
| 10 | D345N | 24 | 1 0.00012% | 0.3149 | MDS | No | |||||
| 11 | D363A | 34 | 0 | 0.6209 | MDS | No | |||||
| 12 | M | R370H | 45 | 0 | 0.881 | Neutropenia | 0 | Yes (SF) | None (blood at 18 y) | ||
| Pancytopenia | 18 | ||||||||||
| 13 | M | R370P | 44 | 0 | 0.888 | MDS (asymptomatic thrombocytopenia and leukopenia) | Deformation (avascular necrosis) of femoral head, severe aortic valve insufficiency with secondary heart failure | 29 | Yes (hair) | None | No |
| 14 | M | Y372∗ | 48 | 0 | NA | Congenital pancytopenia, and BMF | 0 | Yes (de novo) (PB) | |||
| 15 | F | Y373C | 30 | 0 | 0.852 | AML, thrombocytopenia, and t-MDS (RAEB2) | Not reported in clinical records | 27 | Yes (hair) | IDH1 (R132C) (40%) TP53 (C238Y) (22%) GATA2 (H442Qfs∗95) (20%) | Yes |
| 16 | M | Y373C | 17 | 0 | 0.852 | Thrombocytopenia and neutropenia | Not reported in clinical records | 21 | Yes (inherited) (hair) | RUNX1 (G165V) (2%) | Yes (2 events) |
| 17 | M | Y373C | 44 | 0 | 0.852 | Thrombocytopenia and neutropenia | Not reported in clinical records | 19 | Yes (inherited) (hair) | None | Yes |
| 18 | K380N | 46 | 0 | 0.642 | Anemia, thrombocytopenia, pancytopenia, macrocytic anemia, abnormality of the spleen, and eosinophilic infiltration of the esophagus | Hemangioma, hepatosplenomegaly, gastrointestinal inflammation, erythema, and capillary malformation | >18 | Yes (de novo) (PB) | No | ||
| 19 | F | Y388C | 50 | 0 | 0.90 | None | Lymphedema | 8 | Yes (inherited) (PB) | No | |
| 20 | F | Y388C | 33 | 0 | 0.90 | None | Lymphedema (bilateral intermittent lower limb swelling) | 50 | Yes (PB) | Yes | |
| 21 | G394W | 15 | 0 (3× G394R) | 0.661 | t-AML after treatment for DLBCL and prostate cancer | DLBCL and prostate cancer | Yes (PB) | No | |||
| Population | M219I | 372 0.023% (1 hom) | 0.058 | NA | Yes | ||||||
| Population | P275S | 254 0.016% (3 hom) | 0.223 | NA | Yes | ||||||
| Mouse | S322P | 0 | 0.574 | ALL and thrombocytopenia | Yes | ||||||
| ETV6 | R370S | 0 | 0.803 | ALL | No | ||||||
| COSMIC | R385H | 0 (2× R385C) | 0.674 | NA | 2× BrCa, 1× biliary, 1× upper aerodigestive tract | No | |||||
| Population | P404A | 236 0.015% | 0.086 | NA | Yes |
| Patient no. . | Sex . | ERG variant (479 aa) . | VAF (%) . | gnomAD v4.0.0 . | REVEL . | Hematological-related phenotype . | Nonhematological phenotype . | Age onset of first phenotype (y) . | Germ line ERG (inherited/de novo) (Sample) . | Somatic variants . | Chr 21q cnLOH . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | E20Vfs∗13 | 60 | 0 | NA | MDS | 38 | Yes (MSC) | No | ||
| 2 | F | P116R | 56 | 69 0.004% | 0.36 | Thrombocytopenia, thrombocytopathy, and platelet aggregation disorder | Hypertension, diabetes, cataract | 73 | No | ||
| 3 | V127Efs∗82 | 50 | 0 | NA | ALL | <18 | Yes | ||||
| 4 | I126T | 59 | 1 0.00016% | 0.512 | Chronic thrombocytopenia | Not reported in clinical records | <14 | Yes (SF) | FLT3-ITD and IDH1 | ||
| AML | 40 | ||||||||||
| 5 | M | R302C | 40 | 10 0.00068% (1× R302L) (17× R302H) | 0.365 | CLL | Not reported in clinical records | Unknown | Yes (hair) | ||
| 6 | F | P306L | 44 | 0 (6× P306W) | 0.394 | None | Lymphedema | <1 | Yes (inherited) (PB) | No | |
| 7 | M | P306L | 57 | 0 (6× P306W) | 0.394 | None | Lymphedema | Yes | |||
| 8 | F | M341V | 45 | 0 | 0.45 | Severe congenital aplasia and abnormal B cells | Prematurity for acute fetal distress (33 wk) | 0 | Yes (inherited) (SF) | None | |
| 9 | F | M341V | 45 | 0 | 0.45 | MDS | 56 | No | |||
| 10 | D345N | 24 | 1 0.00012% | 0.3149 | MDS | No | |||||
| 11 | D363A | 34 | 0 | 0.6209 | MDS | No | |||||
| 12 | M | R370H | 45 | 0 | 0.881 | Neutropenia | 0 | Yes (SF) | None (blood at 18 y) | ||
| Pancytopenia | 18 | ||||||||||
| 13 | M | R370P | 44 | 0 | 0.888 | MDS (asymptomatic thrombocytopenia and leukopenia) | Deformation (avascular necrosis) of femoral head, severe aortic valve insufficiency with secondary heart failure | 29 | Yes (hair) | None | No |
| 14 | M | Y372∗ | 48 | 0 | NA | Congenital pancytopenia, and BMF | 0 | Yes (de novo) (PB) | |||
| 15 | F | Y373C | 30 | 0 | 0.852 | AML, thrombocytopenia, and t-MDS (RAEB2) | Not reported in clinical records | 27 | Yes (hair) | IDH1 (R132C) (40%) TP53 (C238Y) (22%) GATA2 (H442Qfs∗95) (20%) | Yes |
| 16 | M | Y373C | 17 | 0 | 0.852 | Thrombocytopenia and neutropenia | Not reported in clinical records | 21 | Yes (inherited) (hair) | RUNX1 (G165V) (2%) | Yes (2 events) |
| 17 | M | Y373C | 44 | 0 | 0.852 | Thrombocytopenia and neutropenia | Not reported in clinical records | 19 | Yes (inherited) (hair) | None | Yes |
| 18 | K380N | 46 | 0 | 0.642 | Anemia, thrombocytopenia, pancytopenia, macrocytic anemia, abnormality of the spleen, and eosinophilic infiltration of the esophagus | Hemangioma, hepatosplenomegaly, gastrointestinal inflammation, erythema, and capillary malformation | >18 | Yes (de novo) (PB) | No | ||
| 19 | F | Y388C | 50 | 0 | 0.90 | None | Lymphedema | 8 | Yes (inherited) (PB) | No | |
| 20 | F | Y388C | 33 | 0 | 0.90 | None | Lymphedema (bilateral intermittent lower limb swelling) | 50 | Yes (PB) | Yes | |
| 21 | G394W | 15 | 0 (3× G394R) | 0.661 | t-AML after treatment for DLBCL and prostate cancer | DLBCL and prostate cancer | Yes (PB) | No | |||
| Population | M219I | 372 0.023% (1 hom) | 0.058 | NA | Yes | ||||||
| Population | P275S | 254 0.016% (3 hom) | 0.223 | NA | Yes | ||||||
| Mouse | S322P | 0 | 0.574 | ALL and thrombocytopenia | Yes | ||||||
| ETV6 | R370S | 0 | 0.803 | ALL | No | ||||||
| COSMIC | R385H | 0 (2× R385C) | 0.674 | NA | 2× BrCa, 1× biliary, 1× upper aerodigestive tract | No | |||||
| Population | P404A | 236 0.015% | 0.086 | NA | Yes |
Rare ERG variants (NP_891548.1) from similar phenotypic groups, including BMF and/or HM and lymphedema, among population variants (gnomAD >200),38 a germ line thrombocytopenic mouse mutation,1 a paralogous ETV6 pathogenic variant (thrombocytopenia),49 and COSMIC mutation (somatic).41 Information unavailable (blank); gnomAD v4.0.0, alternative variants at the same amino acid position (brackets).
Chr, chromosome; CLL, chronic lymphocytic leukemia; COSMIC, Catalogue Of Somatic Mutations In Cancer; DLBCL, diffuse large B-cell lymphoma; F, female; hom, homozygous; M, male; NA, not applicable; MSC, mesenchymal stromal cells; PB, peripheral blood; REVEL, Rare Exome Variant Ensemble Learner; SF, skin fibroblasts; t-MDS, therapy-related myelodysplastic syndrome.