What is the interpretation of a CTC (Circulating Tumor Cell) variant heterozygous on whole exome sequencing?

From the Guidelines

Interpreting a heterozygous CTC variant on whole exome sequencing requires genetic counseling and expert evaluation, as the clinical significance depends on several factors including the specific gene involved, the location of the variant within the gene, and whether it's a known pathogenic mutation or a variant of uncertain significance. This finding means one copy of a gene contains a CTC sequence variation while the other copy is normal. The interpretation of such variants can be complex and may involve considerations of germline versus somatic origins, as discussed in studies such as 1, which highlights the importance of distinguishing between germline mutations and somatic clonal hematopoiesis events.

Key factors to consider include:

• The specific gene involved and its known association with disease
• The location of the variant within the gene and its potential impact on gene function
• Whether the variant is a known pathogenic mutation or a variant of uncertain significance
• The presence of any secondary germline testing in cancer genomics, as discussed in 1
• The management of individuals with germline pathogenic/likely pathogenic variants, as outlined in guidelines such as those provided by the American College of Medical Genetics and Genomics (ACMG) for CHEK2 variants 1

I recommend consulting with a medical geneticist or genetic counselor who can properly contextualize this finding within your personal and family medical history. They will determine if additional testing is needed, such as segregation analysis in family members or functional studies to clarify the variant's impact. The interpretation may also change over time as more information becomes available in genetic databases. Remember that heterozygous variants can be benign polymorphisms with no health implications, disease-causing mutations that follow dominant inheritance patterns, or carrier states for recessive conditions. Without knowing the specific gene and variant details, it's impossible to provide more precise guidance, which is why professional genetic consultation is essential for proper clinical management, as emphasized by best practices for variant calling in clinical sequencing 1.

From the Research

Interpretation of CTC Variant Heterozygous on Whole Exome Sequencing

• The interpretation of CTC variant heterozygous on whole exome sequencing can be complex and requires careful analysis of the genetic data 2.
• Whole exome sequencing can identify pathogenic variants in established disease genes, as well as variants of uncertain significance 3.
• In the context of cardiovascular disease, whole exome sequencing has identified truncating variants in nuclear envelope genes, including NUP37, NUP43, and NUP188 3.
• For cancer diagnosis and treatment, whole exome sequencing of circulating tumor cells (CTCs) can explore platinum-drug resistance mutations in advanced non-small cell lung cancer 4.
• The combination of whole exome sequencing with RNA sequencing can reveal compound heterozygous variants in genes such as ATM, which is associated with ataxia-telangiectasia 5.
• The analysis of whole exome sequencing data requires careful consideration of variant annotation, classification, and prioritization, as well as gene annotations that may help establish a relationship between genes and the phenotype in question 2.
• In the case of CTSC variants, homozygous or compound heterozygous variants can cause severe periodontitis, and whole exome sequencing can identify novel missense variants that disrupt protein structure and are predicted to be disease-causing 6.