Somatic variants are gene changes which accumulate over the lifetime of an individual due to factors such as age, lifestyle or environmental factors. As a cell becomes cancerous, the process of acquiring somatic variants accelerates. Tumour testing for somatic variants is undertaken to determine diagnosis, prognosis or treatment options. Somatic variants are only present in the cancer cells and cannot be passed on from parent to child. Therefore, other family members are not at risk of having inherited these variants.
Germline variants (inherited or de novo)
Germline variants are present from conception and are in every cell of the body. In most cases, germline variants are inherited from a parent. However, sometimes they can occur in an individual for the first time in their family (a de novo variant). If a person has a germline variant, they can pass it on to their children. Germline variants can be identified during testing of tumour tissue and can have contributed to the development of the cancer or be an incidental finding.
In some cases, a variant may be present from birth in some but not all the cells of the body. This is known as mosaicism. If the variant is present in the egg or the sperm (known as gonadal mosaicism) it can be passed on from parent to child.
In the table below, an “associated tumour” refers to a tumour/cancer known to be associated with a germline pathogenic variant in the relevant gene.
When a variant is identified, the testing laboratory applies criteria to assess whether the variant is clinically relevant (pathogenic), clinically irrelevant (benign) or whether this is unable to be determined based on currently available information (a variant of uncertain significance or VUS). This process is known as variant curation. The criteria used for variant curation of germline variants are more stringent than the criteria used for curating somatic variants.
Variant allele frequency (VAF)
VAF represents the number of reads for a particular allele divided by the total number of reads for that locus/gene. In the germline, a VAF of 50% is consistent with a heterozygous state and a VAF of 100% with a homozygous state.
In tumour, a VAF for a germline variant might be less than 50% due to altered number of chromosomes (ploidy), deletions/duplications or reversion events. Conversely, a VAF of 50% is not diagnostic of a germline variant and still requires confirmation. A VAF for a germline variant might be more than 50% due to acquired loss of the normal copy of the gene.
Tumour purity of the sample tested (i.e. proportion comprised of tumour versus normal tissue) can also influence VAF if altered numbers of chromosomes are present.
In the literature, a VAF of 30% or greater for single nucleotide variants (SNVs) and 20% or greater for small insertions and deletions is the recommended threshold for suspecting a variant may be germline. Some laboratories will have different recommended thresholds based on their own internal validation. Not all laboratories report VAF.
The report should be checked for the laboratory’s assessment as to whether a variant might be germline. The laboratory can be contacted for clarification if needed.