Tumor genetic findings that raise suspicion of germ line origin variants
| Presence of a pathogenic or suspicious variant in a gene associated with the patient’s phenotype |
| Examples include CEBPA, RUNX1, and DDX41 in patients with AML and ETV6 and PAX5 in patients with B-ALL |
| Variants that are present at a VAF of ∼30% to 50% but can be lower or higher |
| Variants that remain present in multiple BM or blood samples at a stable VAF |
| “Two hits” in a gene associated with a germ line predisposition (eg, missense or truncating mutations, or deletions of the second gene copy; cnLOH∗ with duplication of the mutated allele) |
| Some of these second hits are deleterious (eg, CEBPA, RUNX1, and DDX41) |
| Others may be protective (eg, somatic reversion mutations in cells with SAMD9/SAMD9L mutations or TERT promoter variants in cells from patients with short telomere disorders) |
| Hypermutator status |
| Observed in Lynch syndrome or constitutional mismatch repair deficiency because of mutations or deletions in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM |
| Cytogenetic findings |
| Monosomy 7 (in patients with germ line GATA2, SAMD9, and SAMD9L mutations, particularly in setting of, but not limited to, pediatric MDS and AML) |
| Low hypodiploid ALL (in patients with LFS with germ line TP53 mutations) |
| Copy number changes in chromosome 1, 3, and 7 (in the hematopoietic cells of patients with Fanconi anemia who are progressing to AML) |
| Additional somatic variants characteristic of leukemias occurring in specific predispositions |
| EIF6, TP53, PRPF8, and CSNK1A1 variants are observed in Shwachman-Diamond syndrome† |
| Founder mutations |
| DDX41: p.M1I (c.3G>A), p.V152G (c.455T>G), p.A500fs (c.1496dup), and p.Y259C (c.776A>G) |
| CHEK2: p.I157T (c.470C>T) and p.T367fs (c.1100delC) |
| BRCA1: p.Q23fs (c.68_69del; also known as c.185delAG) and p.Q1756fs (c.5266dupC) |
| BRCA2: p.S1982fs (c.5946delT) |
| Notably, many additional founder mutations exist. A search in gnomAD for the population frequency can provide this information. |
| Presence of a pathogenic or suspicious variant in a gene associated with the patient’s phenotype |
| Examples include CEBPA, RUNX1, and DDX41 in patients with AML and ETV6 and PAX5 in patients with B-ALL |
| Variants that are present at a VAF of ∼30% to 50% but can be lower or higher |
| Variants that remain present in multiple BM or blood samples at a stable VAF |
| “Two hits” in a gene associated with a germ line predisposition (eg, missense or truncating mutations, or deletions of the second gene copy; cnLOH∗ with duplication of the mutated allele) |
| Some of these second hits are deleterious (eg, CEBPA, RUNX1, and DDX41) |
| Others may be protective (eg, somatic reversion mutations in cells with SAMD9/SAMD9L mutations or TERT promoter variants in cells from patients with short telomere disorders) |
| Hypermutator status |
| Observed in Lynch syndrome or constitutional mismatch repair deficiency because of mutations or deletions in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM |
| Cytogenetic findings |
| Monosomy 7 (in patients with germ line GATA2, SAMD9, and SAMD9L mutations, particularly in setting of, but not limited to, pediatric MDS and AML) |
| Low hypodiploid ALL (in patients with LFS with germ line TP53 mutations) |
| Copy number changes in chromosome 1, 3, and 7 (in the hematopoietic cells of patients with Fanconi anemia who are progressing to AML) |
| Additional somatic variants characteristic of leukemias occurring in specific predispositions |
| EIF6, TP53, PRPF8, and CSNK1A1 variants are observed in Shwachman-Diamond syndrome† |
| Founder mutations |
| DDX41: p.M1I (c.3G>A), p.V152G (c.455T>G), p.A500fs (c.1496dup), and p.Y259C (c.776A>G) |
| CHEK2: p.I157T (c.470C>T) and p.T367fs (c.1100delC) |
| BRCA1: p.Q23fs (c.68_69del; also known as c.185delAG) and p.Q1756fs (c.5266dupC) |
| BRCA2: p.S1982fs (c.5946delT) |
| Notably, many additional founder mutations exist. A search in gnomAD for the population frequency can provide this information. |
cnLOH, copy neutral loss of heterozygosity: a condition in which there is deletion of 1 chromosomal region with duplication of the same region from the paired chromosome.
Note that in some cases, additional somatic variants may represent clonal hematopoiesis and are not necessarily indicative or diagnostic of a hematologic malignancy.