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Upgrading rigor and efficiency of germline cancer gene variant classification for the 2020s

Award Number: R01CA264971
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Upgrading rigor and efficiency of germline cancer gene variant classification for the 2020s - ABSTRACT Since approximately 2010, the scale of clinical cancer predisposition genetic testing has increased dramatically. While a large fraction of sequence variants observed during testing are easily classified as benign or pathogenic, many others – principally missense substitutions, in-frame indels, and splice junction variants – are not easily placed on a spectrum from benign to clearly pathogenic. These are termed Variants of Uncertain Significance (VUS), and the clinical management of families in which they segregate would be improved if they could actually be classified. Consortium efforts to develop methods for evaluation and classification of VUS in BRCA1 and BRCA2 date back to a Breast Cancer Information Core satellite meeting held at the ASHG annual meeting in 2000; and methods that had been developing separately within the breast cancer, colorectal cancer, melanoma, and Li Fraumeni-syndrome genetics communities were cross-pollinated at a 2008 International Agency for Research on Cancer (IARC) working group meeting on VUS in cancer susceptibility genes. However, neither the qualitative nor the quantitative methods that sprouted from that meeting produced a generalizable overall approach. In 2015, the American College of Medical Genetics (ACMG) published guidelines for evaluating VUS across all Mendelian disease susceptibility genes. These guidelines produced a practical VUS evaluation framework that has been adopted by testing labs and organizations around the country. However, the ACMG system is entirely qualitative, with evidence weighted by expert opinion rather than by empirical evidence. Subsequently, we fitted the ACMG system into a quantitative Bayesian framework, providing a route to replacing qualitative evidence criteria from the ACMG system with empirically measured counterparts. Indeed, we hypothesize that there will be clear instances where strength accorded to current ACMG evidence criteria is contradicted by empirical measurement; correcting these will self-evidently improve the rigor of VUS evaluation. Aim 1 will place related ACMG data types into larger, logically consistent sets and then reduce or eliminate hidden dependencies between those sets. Noting that the ACMG variant classification guidelines were almost entirely qualitative, Aim 2 will improve the rigor of calibration for key data types through empirical measurement. Recently, we derived a quantitative Bayesian point-system for VUS evaluation and classification, which is back compatible with its parent quantitative Bayesian framework and the qualitative ACMG variant classification guidelines. Thus Aim 3 will refine this Bayesian point-system, taking advantage of the improved outputs from Aims 1 and 2. Finally, Aim 4 will benchmark elements of VUS evaluation and classification. Successful completion of these Aims will improve rigor in the system used for evaluation of VUS in cancer susceptibility genes, enabling higher throughput VUS evaluation and improving confidence in the resulting classifications.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $468,901 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	5	1/28/2026	NON-COMPETING CONTINUATION	$468,901
														Subtotal = $468,901

Issue Date FY: 2025 ( Subtotal = $552,001 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	001	4	9/23/2025	NON-COMPETING CONTINUATION	$48,508
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	4	1/28/2025	NON-COMPETING CONTINUATION	$503,493
														Subtotal = $552,001

Issue Date FY: 2024 ( Subtotal = $520,538 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	3	1/11/2024	NON-COMPETING CONTINUATION	$493,140
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$27,398
														Subtotal = $520,538

Issue Date FY: 2023 ( Subtotal = $758,956 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Trans-NIH Research Support	001	2	9/14/2023	SUPPLEMENT FOR EXPANSION	$220,416
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$538,540
														Subtotal = $758,956

Issue Date FY: 2022 ( Subtotal = $590,708 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Cause and Prevention Research	000	1	2/21/2022	NEW	$590,708
														Subtotal = $590,708

Grand Total All Awards = $2,891,104

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Upgrading rigor and efficiency of germline cancer gene variant classification for the 2020s

Award Number: R01CA264971

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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