Background

Genetic variant databases play an essential role in driving precision oncology. Well annotated databases aid in offering evidence-based classification of variants for clinical actionability - including for diagnosis, therapy guidance and prognosis (e.g. HGMD¹, ClinVar² MarkerDB³, MUSTARD⁴ etc.). However a number of genetic variants, especially from diverse populations are not well represented in such databases, limiting their utility in clinical decision making. Additionally the multiple standards and criteria utilised by diagnostic laboratories to annotate variants as Pathogenic or Benign make the problem more acute, for clinical interpretation of the reports and further genetic counselling and clinical actionability⁶.

India is unique in many aspects, with a diverse and stratified population and admixture with major populations across the world , all contributing significantly to the genetic diversity of the population. The recent initiatives aimed at population-scale sequencing like IndiGen have provided a unique opportunity to understand the prevalence of genetic variants in the population.

While a number of laboratories and genetic testing services offer genetic testing/screening for BRCA1 and BRCA2 genetic variants, the lack of a uniform system followed across the laboratories for the interpretation of the pathogenicity of genetic variants has limited the clinical actionability of variants in clinical settings. Such non-standard approaches have also resulted in inter-clinician and inter-lab differences in interpretation including sometimes conflicting interpretations of genetic variants and their pathogenicity. The ACMG & AMP joint guidelines for the interpretation of pathogenicity of genetic variants is a globally followed system now in place, but due to the fact that the interpretation is time-consuming, tedious and requires careful evaluation of published evidence, is not followed widely in India.

Participating in the collection

Clinical collaborators are encouraged to participate in this endeavour. Collaborators are expected to share genetic variants and classification on pathogenicity (without any personal or identifiable information on the patient) in a predetermined proforma. They could also share entries already submitted to a public database like ClinVar or dbSNP .

For clinicians interested in learning classification of pathogenicity of variants as per the ACMG & AMP Guidelines may also see the GVACI Course

Clinicians contributing towards the endeavour would be duly credited / acknowledged depending on the contributions made to the database.

The compendium of variants and their pathogenicity would be made available to all participants without restrictions along with the reassessed classifications.