TY - JOUR
T1 - The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort
AU - Abu Shtaya, Aasem
AU - Kedar, Inbal
AU - Mattar, Samar
AU - Mahamid, Ahmad
AU - Basel-Salmon, Lina
AU - Farage Barhom, Sarit
AU - Naftaly Nathan, Sofia
AU - Magal, Nurit
AU - Azulay, Noy
AU - Levy Zalcberg, Michal
AU - Chen-Shtoyerman, Rakefet
AU - Segol, Ori
AU - Seri, Mor
AU - Reznick Levi, Gili
AU - Shkedi-Rafid, Shiri
AU - Vinkler, Chana
AU - Netzer, Iris
AU - Hagari Bechar, Ofir
AU - Chamma, Liat
AU - Liberman, Sari
AU - Goldberg, Yael
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - APC
KW - BRCA1
KW - BRCA2
KW - Israel
KW - Lynch
KW - cancer
KW - founder
KW - yield
UR - http://www.scopus.com/inward/record.url?scp=85182189485&partnerID=8YFLogxK
U2 - 10.3390/cancers16010094
DO - 10.3390/cancers16010094
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AN - SCOPUS:85182189485
SN - 2072-6694
VL - 16
JO - Cancers
JF - Cancers
IS - 1
M1 - 94
ER -