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

Sophie Allen; Charlie F. Rowlands; Samantha Butler; Miranda Durkie; Carrie Horton; Tina Pesaran; Marcy Richardson; Rachel Robinson; Alice Garrett; George J. Burghel; Alison Callaway; Joanne Field; Bethan Frugtniet; Sheila Palmer-Smith; Jonathan Grant; Judith Pagan; Trudi McDevitt; Katie Snape; Avgi Andreou; Eamonn R. Maher; Helen Hanson; Terri McVeigh; Clare Turnbull

doi:10.1016/j.gim.2025.101565

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

Sophie Allen
, Charlie F. Rowlands
, Samantha Butler
, Miranda Durkie
, Carrie Horton
, Tina Pesaran
, Marcy Richardson
, Rachel Robinson
, Alice Garrett
, George J. Burghel
, Alison Callaway
, Joanne Field
, Bethan Frugtniet
, Sheila Palmer-Smith
, Jonathan Grant
, Judith Pagan
, Trudi McDevitt
, Katie Snape
, Avgi Andreou
, Eamonn R. Maher

Helen Hanson, Terri McVeigh, Clare Turnbull

Central and South Genomic Laboratory Hub, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, Birmingham, UK.

Research output: Contribution to journal › Article › peer-review

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Abstract

Purpose:
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH.

Methods:
We collated clinical diagnostic testing data on germline FH variants 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), and domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log likelihood 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 in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer, and may be applicable in clinical variant classification.

Original language	English
Article number	101565
Number of pages	12
Journal	Genetics in Medicine
Volume	27
Issue number	11
Early online date	4 Sept 2025
DOIs	https://doi.org/10.1016/j.gim.2025.101565
Publication status	Published - 1 Nov 2025

Bibliographical note

Copyright © 2025 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Data Access Statement

All data generated or analysed during this study are either included in this published article and its supplementary information files, are available from the corresponding author on request, or are publicly available at the references and URLs provided. This research has been conducted using the UK Biobank Resource under Application Number 76689
(https://www.ukbiobank.ac.uk/).

Funding

A full list of CanVIG-UK consortium members and their affiliations appears in the Supplemental Material. The Article Publishing Charge (APC) for this article was paid by the Institute of Cancer Research. This work was made available as a pre-print on medRχiv on 19th March 2025: https://doi.org/10.1101/2025.03.17.25324088. S.A. and C.F.R. are supported by CG-MAVE, CRUK Programme Award [EDDPGM-Nov22/100004]. Funding Statement: A.G. and H.H. are supported by CRUK Catalyst Award CanGene-CanVar (C61296/A27223). E.R.M acknowledges and thanks NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312) and VHL UK/Ireland.

Keywords

variant interpretation
HLRCC
germline
renal cancer
FH

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S Allen et al_Quantifying evidence for phenotypic specificity PP4 for syndromic phenotypes_Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer
Copyright © 2025 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
Final published version, 1.3 MBLicence: CC BY 4.0

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Allen, S., Rowlands, C. F., Butler, S., Durkie, M., Horton, C., Pesaran, T., Richardson, M., Robinson, R., Garrett, A., Burghel, G. J., Callaway, A., Field, J., Frugtniet, B., Palmer-Smith, S., Grant, J., Pagan, J., McDevitt, T., Snape, K., Andreou, A., ... Turnbull, C. (2025). Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer. Genetics in Medicine, 27(11), Article 101565. https://doi.org/10.1016/j.gim.2025.101565

@article{f8d0127d60e6469293eca729dea2fc8c,

title = "Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer",

abstract = "Purpose: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. Methods: We collated clinical diagnostic testing data on germline FH variants 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), and domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log likelihood 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 in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer, and may be applicable in clinical variant classification. ",

keywords = "variant interpretation, HLRCC, germline, renal cancer, FH",

author = "Sophie Allen and Rowlands, \{Charlie F.\} and Samantha Butler and Miranda Durkie and Carrie Horton and Tina Pesaran and Marcy Richardson and Rachel Robinson and Alice Garrett and Burghel, \{George J.\} and Alison Callaway and Joanne Field and Bethan Frugtniet and Sheila Palmer-Smith and Jonathan Grant and Judith Pagan and Trudi McDevitt and Katie Snape and Avgi Andreou and Maher, \{Eamonn R.\} and Helen Hanson and Terri McVeigh and Clare Turnbull",

note = "Copyright {\textcopyright} 2025 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).",

year = "2025",

month = nov,

day = "1",

doi = "10.1016/j.gim.2025.101565",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

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Allen, S, Rowlands, CF, Butler, S, Durkie, M, Horton, C, Pesaran, T, Richardson, M, Robinson, R, Garrett, A, Burghel, GJ, Callaway, A, Field, J, Frugtniet, B, Palmer-Smith, S, Grant, J, Pagan, J, McDevitt, T, Snape, K, Andreou, A, Maher, ER, Hanson, H, McVeigh, T & Turnbull, C 2025, 'Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer', Genetics in Medicine, vol. 27, no. 11, 101565. https://doi.org/10.1016/j.gim.2025.101565

Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer. / Allen, Sophie; Rowlands, Charlie F.; Butler, Samantha et al.
In: Genetics in Medicine, Vol. 27, No. 11, 101565, 01.11.2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer

AU - Allen, Sophie

AU - Rowlands, Charlie F.

AU - Butler, Samantha

AU - Durkie, Miranda

AU - Horton, Carrie

AU - Pesaran, Tina

AU - Richardson, Marcy

AU - Robinson, Rachel

AU - Garrett, Alice

AU - Burghel, George J.

AU - Callaway, Alison

AU - Field, Joanne

AU - Frugtniet, Bethan

AU - Palmer-Smith, Sheila

AU - Grant, Jonathan

AU - Pagan, Judith

AU - McDevitt, Trudi

AU - Snape, Katie

AU - Andreou, Avgi

AU - Maher, Eamonn R.

AU - Hanson, Helen

AU - McVeigh, Terri

AU - Turnbull, Clare

N1 - Copyright © 2025 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

PY - 2025/11/1

Y1 - 2025/11/1

N2 - Purpose: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. Methods: We collated clinical diagnostic testing data on germline FH variants 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), and domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log likelihood 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 in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer, and may be applicable in clinical variant classification.

AB - Purpose: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This paper quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. Methods: We collated clinical diagnostic testing data on germline FH variants 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), and domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log likelihood 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 in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer, and may be applicable in clinical variant classification.

KW - variant interpretation

KW - HLRCC

KW - germline

KW - renal cancer

KW - FH

UR - https://www.sciencedirect.com/science/article/pii/S1098360025002126

UR - https://www.scopus.com/pages/publications/105017906131

U2 - 10.1016/j.gim.2025.101565

DO - 10.1016/j.gim.2025.101565

M3 - Article

C2 - 40916913

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

M1 - 101565

ER -

Allen S, Rowlands CF, Butler S, Durkie M, Horton C, Pesaran T et al. Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC (Hereditary Leiomyomatosis and Renal Cell Cancer) and renal cancer. Genetics in Medicine. 2025 Nov 1;27(11):101565. Epub 2025 Sept 4. doi: 10.1016/j.gim.2025.101565

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

Abstract

Bibliographical note

Data Access Statement

Funding

Keywords

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