Clinical considerations for germline predisposition testing
| Clinical considerations regarding germline predisposition testing . | ||
|---|---|---|
| WHO? | Individual with ≥2 cancers, 1 of which is an HM | |
| OR | ||
| Individual with a history of an HN AND | ||
| A relative within 2 generations diagnosed with an HN, OR | ||
| A relative within 2 generations diagnosed with a solid tumor at age ≤50, OR | ||
| A relative within 2 generations diagnosed with another hematopoietic abnormality | ||
| OR | ||
| Individual whose tumor-based molecular profiling identified a deleterious variant with a VAF consistent with germline status∗ | ||
| OR | ||
| HM diagnosis at a much younger age than is typical | ||
| IDEAL AGE for testing? | Individuals of all ages should be considered for germline predisposition testing because some gene variants drive myeloid malignancies even at advanced ages (e.g., DDX41) | |
| WHAT SAMPLE? | Ideal: | Gold standard cultured skin fibroblasts (some clinical laboratories also accept BM-derived mesenchymal stromal cells) |
| Possible: | Skin biopsy, with washout of PB | |
| Hair follicles (may not yield sufficient DNA for comprehensive testing) | ||
| Buccal swab (may have low-level PB contamination) | ||
| Not recommended: | Saliva (highly contaminated with PB) | |
| Fingernails (may be contaminated with monocytes) | ||
| WHAT TEST?† | WES augmented with spike-in probes for noncoding regions known to contain predisposition loci followed by analysis of gene groups | |
| WGS (if available), with a virtual panel of appropriate genes, including noncoding regions and copy number variation studies | ||
| Panel-based NGS | ||
| COMPLEMENTARY testing | Telomere flow–FISH can identify individuals with short-telomere syndromes, although interpretation can be confounded by active disease and/or treatment | |
| Diepoxybutane and mitomycin C analyses identify excessive chromosome breakage and assist in the diagnosis of FA | ||
| HOW can you tell if a variant is germline? | Variant is present in DNA derived from a preferred tissue source (see above) at a VAF consistent with germline status∗ OR | |
| Variant is present in the index patient plus one other relative at a VAF consistent with germline∗ | ||
| WHEN? | At HN diagnosis | |
| At recognition of a potential germline allele from tumor or other screening, including somatic variants suggestive of an underlying germline variant (eg, R525H-encoding variant in DDX41) | ||
| before HSCT using a relative as a donor | ||
| WHY? | Plan surveillance for other cancers or organ dysfunction | |
| Plan HSCT using a related donor | ||
| Allow pre-implantation genetic testing | ||
| Cascade testing throughout the family | ||
| Clinical considerations regarding germline predisposition testing . | ||
|---|---|---|
| WHO? | Individual with ≥2 cancers, 1 of which is an HM | |
| OR | ||
| Individual with a history of an HN AND | ||
| A relative within 2 generations diagnosed with an HN, OR | ||
| A relative within 2 generations diagnosed with a solid tumor at age ≤50, OR | ||
| A relative within 2 generations diagnosed with another hematopoietic abnormality | ||
| OR | ||
| Individual whose tumor-based molecular profiling identified a deleterious variant with a VAF consistent with germline status∗ | ||
| OR | ||
| HM diagnosis at a much younger age than is typical | ||
| IDEAL AGE for testing? | Individuals of all ages should be considered for germline predisposition testing because some gene variants drive myeloid malignancies even at advanced ages (e.g., DDX41) | |
| WHAT SAMPLE? | Ideal: | Gold standard cultured skin fibroblasts (some clinical laboratories also accept BM-derived mesenchymal stromal cells) |
| Possible: | Skin biopsy, with washout of PB | |
| Hair follicles (may not yield sufficient DNA for comprehensive testing) | ||
| Buccal swab (may have low-level PB contamination) | ||
| Not recommended: | Saliva (highly contaminated with PB) | |
| Fingernails (may be contaminated with monocytes) | ||
| WHAT TEST?† | WES augmented with spike-in probes for noncoding regions known to contain predisposition loci followed by analysis of gene groups | |
| WGS (if available), with a virtual panel of appropriate genes, including noncoding regions and copy number variation studies | ||
| Panel-based NGS | ||
| COMPLEMENTARY testing | Telomere flow–FISH can identify individuals with short-telomere syndromes, although interpretation can be confounded by active disease and/or treatment | |
| Diepoxybutane and mitomycin C analyses identify excessive chromosome breakage and assist in the diagnosis of FA | ||
| HOW can you tell if a variant is germline? | Variant is present in DNA derived from a preferred tissue source (see above) at a VAF consistent with germline status∗ OR | |
| Variant is present in the index patient plus one other relative at a VAF consistent with germline∗ | ||
| WHEN? | At HN diagnosis | |
| At recognition of a potential germline allele from tumor or other screening, including somatic variants suggestive of an underlying germline variant (eg, R525H-encoding variant in DDX41) | ||
| before HSCT using a relative as a donor | ||
| WHY? | Plan surveillance for other cancers or organ dysfunction | |
| Plan HSCT using a related donor | ||
| Allow pre-implantation genetic testing | ||
| Cascade testing throughout the family | ||
HN, hematopoietic neoplasm.
Generally considered to be a VAF between 30% to 60% when tested on an appropriate sample type.
Genes curated as those in which deleterious variants confer risk for hematopoietic malignancies are increasing in number. Resources that delineate up to date genes to consider for testing include: https://dnatesting.uchicago.edu/ and https://panelapp.genomicsengland.co.uk/panels/59/. Several biases regarding testing need to be kept in mind and considered. There may be ascertainment bias in some publications, with gene variants described in a cancer cohort but not in a control, noncancer cohort, resulting in a study that lacks a comparison of an observed variant frequency vs an expected variant frequency. Confounding factors, such as age, prior genotoxic therapies, and other familial factors, may contribute to cancer risk along with that conferred by the germline variant. Pathologic classifications of myeloid malignancies, including myelodysplastic syndromes, clonal cytopenias, and clonal hematopoiesis, shift over time and may complicate interpretations of individual and family histories.