Recombinational DNA Repair - Science topic

Recently, I had some discussion with another colleague about the classification of variants detected in our routine clinical care. Here's an example, the gene A is involved in homologous recombination repair, truncating mutation in A increased the risk of developing breast/ovarian cancer, or other cancers.We detected a missense variant in gene A, but the population frequency of this variant, let's say 1.5%, is higher than the occurance of this risease (3/10000)； meanwhile, there are other evidence, functional study or in silico prediction, show that the change leads to HR defect.

In my personal perspective, I woud give a higher weight to the population frequency. Although functional study or in silico prediction shows this variant leads to HRD, the carriers didn't show increased cancer risk; therefore, I would consider this variant as benign OR likely benign.

My colleague, however, has a different opinion that she would like to classify this variant as VUS (variant of unknown significance), since the evidence from population frequency and functional consequences are contradict to each other.

May I know your opinion ? I would appreciate your sharing.

Dear Investigator,

The comet assay has been in existence for many years, but the general protocol largely remains unchanged, despite it requiring numerous, time-consuming steps. We in the Oxidative Stress Group, at Florida International University, are very interested in learning about comet assay users’ experiences, and their thoughts on the protocol. Below is a link to a short questionnaire that we would be grateful if you would complete. All replies are entirely anonymous, but you will have the opportunity be entered into a prize draw for an Amazon voucher.

https://fiu.qualtrics.com/jfe/form/SV_dh9MYqcgHp42LoV

(you might need to cut and paste into browser.)

Feel free to distribute to other colleagues who may be interested.

Please feel free to contact any of us if you have any questions, or want to confirm the veracity of this email and questionnaire.

Thank you very much in advance,

Marcus

Professor and Head of Department.

Oxidative Stress Group, Dept. Environmental & Occupational Health,

Florida International University, Miami, FL 33199.

Hi everybody,

53BP1 is known to block single strand resection which is an essential mechanism for the Homologous Repair DNA pathway, and by consequence, promotes the NHEJ pathway. In BRCA1 mutated cells, Inhibition of 53BP1 favor a reactivation of HR pathway. The consequence is an apparition of PARP inhibitors resistance. My question is, if the inhibition of 53BP1 promotes the HR pathway, why is there a resistance with PARPi (which promote ssDNA breaks and after dsDNA breaks) but seems to improve the IR hypersensitivity of cells (which triggers ssDNA and dsDNA breaks as well) ? I'm really confused about that and I don't if I am enough clear in my question. So don't hesitate to ask me to be more clear :)

Thank you for your help