Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients

Tsaousis, Georgios N.; Papadopoulou, Eirini; Αγιαννιτόπουλος, Κωνσταντίνος; Pepe, Georgia; Tsoulos, Nikolaos; Boukovinas, Ioannis; Floros, Theofanis; Iosifidou, R.; Katopodi, Ourania; Koumarianou, Anna; Markopoulos, Christos; Papazisis, Konstantinos; Venizelos, V.; Kapsimalis, Achilleas; Xepapadakis, Grigorios; Psyrri, Amanda; Banu, E.; Eniu, Dan Tudor; Blidaru, Alexandru; Stănculeanu, Dana Lucia; Ungureanu, Andrei; Özmen, Vahit; Tansan, Sualp; Tekinel, Mehmet; Yalçın, Şuayib; Nasioulas, George

doi:10.21873/cgp.20304

Cited by 8 publications

(6 citation statements)

References 53 publications

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“…The biological significance of genetic variants and their implications for cancer risk render an essential role in medical diagnosis and treatment. In circumstances where a genetic variant is a matter of controversy or has doubt regarding its clinical consequences, it will be crucial to raise the concern in the appropriate outcome report [ 25 ]. In the case we presented, the patient had a history of a partial oophorectomy, so during the initial post-test genetic counseling and in contemplating a molecular result related to LS, the possibility of performing a contralateral-oophorectomy was evaluated according to management guidelines [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer

Fragoso-Ontiveros

Fuente-Hernandez

Gonzalez-Osnaya

et al. 2023

IJMS

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The PMS2 gene is involved in DNA repair by the mismatch repair pathway. Deficiencies in this mechanism have been associated with Lynch Syndrome (LS), which is characterized by a high risk for colorectal, endometrial, ovarian, breast, and other cancers. Germinal pathogenic variants of PMS2 are associated with up to 5% of all cases of LS. The prevalence is overestimated for the existence of multiple homologous pseudogenes. We report the case of a 44-year-old woman diagnosed with breast cancer at 34 years without a relevant cancer family history. The presence of pathogenic variant NM_000535.7:c.1A > T, (p.Met1Leu) in PMS2 was determined by next-generation sequencing analysis with a panel of 322 cancer-associated genes and confirmed by capillary sequencing in the patient. The variant was determined in six family members (brothers, sisters, and a son) and seven non-cancerous unrelated individuals. Analysis of the amplified region showed high homology of PMS2 with five of its pseudogenes. We determined that the variant is associated with the PMS2P1 pseudogene following sequence alignment analysis. We propose considering the variant c.1A > T, (p.Met1Leu) in PMS2 for reclassification as not hereditary cancer-related, given the impact on the diagnosis and treatment of cancer patients and families carrying this variant.

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Section: Discussionmentioning

confidence: 99%

A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer

Fragoso-Ontiveros

Fuente-Hernandez

Gonzalez-Osnaya

et al. 2023

IJMS

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“…The advances in DNA sequencing technologies and the decreased costs of genetic assays lead to expressive increase in the number of genes incorporated in genetic testing for BC risk prediction ( 20 ). Most gene panels include high-penetrance genes, such as BRCA1 , BRCA2 , CDH1 , PALB2 , PTEN , STK11 , and TP53 , and moderate-penetrance genes, such as ATM , BRIP1 , CHEK2 , FANCD2 , RAD51C , NBN , and PMS2 , which also associates with lifetime BC risk ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer

et al. 2022

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Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.

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“…Der Einsatz der NGS-Multi-Genpanel-Analyse im Rahmen der Keimbahnmutationstestung bei Brustkarzinom ermöglicht eine Abschätzung des Krebsrisikos und davon abgeleitete, risikominimierende therapeutische Maßnahmen. BRCA1, BRCA2, PALB2, PTEN und TP53 sind mit hohem, ATM, CHEK2 und NBN mit moderatem und MLH1, MSH2, MSH6, RAD51C mit niedrigem Brustkarzinomrisiko assoziiert [23].…”

Section: Merkeunclassified

Klinische Anwendungsbeispiele einer Next-Generation-Sequencing-basierten Multi-Genpanel-Analyse

Enko,

Schaflinger,

Müller

2023

TumorDiagnostik & Therapie

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ZusammenfassungDieser Übersichtsartikel bietet einen Überblick über klinisch sinnvolle Anwendungsgebiete einer Next-Generation-Sequencing-basierten (NGS) Multi-Genpanel-Teststrategie in den Bereichen Onkologie, hereditärer Tumorsyndrome und Hämatologie. Bei soliden Tumoren (z.B. Lungenkarzinom, Kolonrektalkarzinom) trägt die Detektion somatischer Mutationen nicht nur zu einer besseren diagnostischen, sondern auch therapeutischen Stratifizierung der Betroffenen bei. Die zunehmende genetische Komplexität hereditärer Tumorsyndrome (z.B. Brust- und Ovarialkarzinom, Lynchsyndrom/Polypose) erfordert in betroffenen Familien eine Multi-Genpanel-Analyse von Keimbahnmutationen. Ein weiteres sinnvolles Indikationsgebiet einer Multi-Genpanel-Diagnostik und Prognoseabschätzung sind akute und chronische myeloische Erkrankungen. Die Kriterien der WHO-Klassifikation und des „European LeukemiaNet“-Prognosesystems der akuten myeloischen Leukämie können nur durch eine Multi-Genpanel-Teststrategie erfüllt werden.

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Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients

Cited by 8 publications

References 53 publications

A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer

A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer

Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer

Klinische Anwendungsbeispiele einer Next-Generation-Sequencing-basierten Multi-Genpanel-Analyse

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