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. 2023 Dec 24;16(1):94.
doi: 10.3390/cancers16010094.

The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort

Aasem Abu Shtaya  1   2 , Inbal Kedar  1 , Samar Mattar  3 , Ahmad Mahamid  3 , Lina Basel-Salmon  1   4   5   6 , Sarit Farage Barhom  1 , Sofia Naftaly Nathan  1 , Nurit Magal  1 , Noy Azulay  1 , Michal Levy Zalcberg  7 , Rakefet Chen-Shtoyerman  8   9 , Ori Segol  2 , Mor Seri  1 , Gili Reznick Levi  10 , Shiri Shkedi-Rafid  11 , Chana Vinkler  12 , Iris Netzer  13 , Ofir Hagari Bechar  1 , Liat Chamma  1 , Sari Liberman  14 , Yael Goldberg  1   4
Affiliations

The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort

Aasem Abu Shtaya et al. Cancers (Basel). .

Abstract

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020-January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.

Keywords: APC; BRCA1; BRCA2; Israel; Lynch; cancer; founder; yield.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Results of targeted FVT in the cohort.
Figure 2
Figure 2
Founder variants detected in the cohort.
See this image and copyright information in PMC

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