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Table 1 Glossary

From: Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

1. Variant: any change in DNA sequence.
2. Pathogenic or likely pathogenic variant (PV): change in DNA sequence that alters the function of a gene (i.e., a variant that predisposes to disease, in this case cancer). Often referred to as a “mutation.”
3. Germline genetic testing: testing germline DNA (generally blood leukocytes) for inherited PVs.
4. Somatic genomic testing of tumor: testing a tumor for variants and PVs, either by tumor biopsy or circulating free DNA.
5. Minor allele frequency (MAF): the relative frequency of the allele with the variant (or PV) in a population, expressed as a fraction or percentage. A low MAF (< 25–35%, depending on the commercial laboratory) is suggestive of a somatic, rather than germline, PV.
6. Germline PV: a heritable change in the DNA that is present in a germ cell (egg or in the sperm). When transmitted to a child, a germline PV is incorporated in every cell of the offspring.
7. Somatic PV: a post-zygotic alteration in DNA that occurs during embryonic development or later in a person’s life. Somatic PVs can occur in any of the cells of the body, and unless they also involve the germ cells (sperm or egg), they are not heritable. Tumor-specific PVs are a type of somatic PV.
8. Mosaicism: the presence of at least two cell lines differing in genotype, derived from the same zygote.
9. Somatic (classic) mosaicism: the somatic cells of the body are of more than one genotype. This results from a PV that occurred post-zygote or a nondisjunction event in an early mitosis.
10. Clonal hematopoiesis (CH): a PV in a subpopulation (clone) of the hematopoietic cells but not in other tissues.
11. Germline (gonadal) mosaicism: a type of genetic mosaicism where more than one set of genetic information is found in an individual, specifically within their gamete cells due to a PV that occurred after conception. The offspring will have a germline PV with a variant allele frequency of ~ 50%. The parent with the gamete PV will not appear to have a PV from standard genetic testing. The offspring will appear to have a de novo germline PV.
12. De novo PV: a PV that is present for the first time in an individual but is not detectable in the blood of either parent. This can be the result of a PV in a gamete cell (egg or sperm) of one parent (gonadal mosaicism), or that arises in the fertilized egg itself during very early embryogenesis.
13. Depth of sequencing: coverage (or depth) in DNA sequencing is the number of unique reads that include a given nucleotide, a particular DNA sequence. Deep sequencing refers to the general concept of aiming for a high number of unique reads of each region of a sequence.
14. Proband: a person who serves as the starting point for genetic evaluation of a family.