Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germlineFHvariants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer

  1. Sophie Allen
  2. Charlie F. Rowlands
  3. Samantha Butler
  4. Miranda Durkie
  5. Carrie Horton
  6. Tina Pesaran
  7. Marcy Richardson
  8. Rachel Robinson
  9. Alice Garrett
  10. George J. Burghel
  11. Alison Callaway
  12. Joanne Field
  13. Bethan Frugtniet
  14. Sheila Palmer-Smith
  15. Jonathan Grant
  16. Judith Pagan
  17. Trudi McDevitt
  18. Katie Snape
  19. Avgi Andreaou
  20. Eamonn R. Maher
  21. Helen Hanson
  22. Terri McVeigh
  23. Clare Turnbull
  24. CanVIG-UK
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Abstract

Purpose

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants inFH. This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants inFH.

Methods

We collated clinical diagnostic testing data on germlineFHvariants from 387 individuals with HLRCC and 1,780 individuals with renal cancer, and compared the frequency of ‘very rare’ variants in each phenotypic cohort against 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08likelihood ratios (LLRs) as applicable within the updated ACMG/AMP Variant Classification Framework.

Results

For HLRCC, the PG-VRV-LR was estimated to be 2,669.4 (95% CI: 1,843.4-3,881.2, LLR 10.77) for truncating variants and 214.7 (185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (48.9-183.0, LLR 6.23) for truncating variants and 5.8 (3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed three ‘hotspot’ regions wherein the DS-VRMV-LR increased to 1226.9.

Conclusion

These data provide quantitative measures for very rare missense and truncating variants inFH, which reflect the differing phenotypic specificity of HLRCC and renal cancer, and may be applicable in clinical variant classification.

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