Splicing and DNA repair
A gene can still produce RNA even when that RNA cannot produce a normal protein. This is why the reports examine BRCA1 sequence, splice junctions, chromosome copies, and repair scars separately.
Splicing edits the RNA message
Exon skipping is one possible abnormal splice product. Its protein consequence depends on the precise transcript; detecting RNA does not prove normal function.
Exons are transcript segments retained after splicing; some exon sequence is untranslated. Introns are intervening segments removed from pre-mRNA. A splice donor marks the start of an intron and a splice acceptor its end. A junction read crosses the join between retained segments and supplies evidence about the RNA product.
A damaged splice site can cause exon skipping, intron retention, or use of a cryptic splice site, an alternative site the processing machinery recognizes. Different products can arise from the same DNA variant. HGVS: splice-variant examples
Decode the variant names
| Example | What the notation says |
|---|---|
| BRCA1 c.81-1G>A | In coding-DNA numbering, G changes to A one intronic base before the exon position numbered 81; it lies at the acceptor boundary |
| TP53 c.559+2T>G | T changes to G two intronic bases after exon position 559; it lies at the donor boundary |
| p.S382* | At protein position 382, serine is replaced by a stop signal; this is a nonsense change, not automatically a frameshift |
These abbreviated names require a reference transcript and version for exact interpretation. A genome build such as GRCh37 or GRCh38 defines genomic coordinates; chromosome positions should never be compared without checking that reference. HGVS: sequence numbering
Proteins are read in groups of three RNA bases. A frameshift changes that grouping. A premature termination codon, or early stop, can lead to shortened protein or nonsense-mediated decay (NMD), a process that removes certain transcripts. NMD depends on transcript context; an early-stop prediction does not prove decay occurred. RNA-surveillance explanation
What HRD records
Homologous recombination (HR) repairs DNA using a matching template. HRD means deficiency in that repair system. BRCA1/BRCA2 disruption can cause it, but the gene name, a genomic scar, and measured current repair function are different evidence layers.
| Report term | What it describes |
|---|---|
| Genomic scar | Persistent DNA/chromosome patterns accumulated during tumor evolution |
| LST | Large-scale transitions: boundaries between large chromosome segments under the method's rules |
| TAI | Telomeric allelic imbalance: unequal parental contributions in regions extending toward chromosome ends |
| LOH scar component | Selected broad regions that have lost one inherited version; distinct from a single gene's copy state |
| SBS3 | A fitted single-base-substitution pattern associated with HRD; the mutation set and fitting choices affect its estimate |
| RAD51 foci | Clusters of repair protein used in functional research assays; interpretation requires suitable cells, damage, and assay controls |
The October 4 analysis reports scar sums of 67–99 across plausible copy-number fits. Earlier 62/72 values should not be carried forward as current validated scores. Scars can remain after repair function changes. October 4 copy-number report, RAD51 primary study
Microhomology is a short matching DNA sequence at joined break ends. POLQ encodes polymerase theta, involved in a backup end-joining route. Experiments show HR-deficient models can depend on this route; high POLQ RNA alone does not demonstrate that dependence. Replication stress means difficulty copying DNA; ATR helps coordinate the response to that stress. These are mechanistic research questions, not interchangeable HRD tests. Ceccaldi et al., Mateos-Gomez et al.
Say it in your own words
“The splice evidence helps explain how BRCA1 RNA may be disrupted. The scars record the tumor's repair history. Protein and functional testing answer whether the repair defect is still present.”
Check yourself: Does detectable BRCA1 RNA prove intact BRCA1 function? No. Its sequence, processing, protein product, and function matter. Next: immune recognition.