Optimising clinical care through -specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

BACKGROUND

Germline pathogenic variants in are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) Variant Curation Expert Panel (VCEP) developed specifications for variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.

METHODS

variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing variant curations. The VCEP reviewed 273 variants using updated specifications and incorporated published and unpublished data provided by diagnostic laboratories.

RESULTS

Updated -specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.

CONCLUSIONS

The development and evolution of specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.