Abstract
Purpose: A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population. Patients and Methods: Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del. Results: We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message. Conclusion: We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
| Original language | English |
|---|---|
| Pages (from-to) | 26-31 |
| Number of pages | 6 |
| Journal | Journal of Clinical Oncology |
| Volume | 26 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2008 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. / Malacrida, Sandro; Agata, Simona; Callegaro, Monia; Casella, Cinzia; Barana, Daniela; Scaini, Maria C.; Manoukian, Siranoush; Oliani, Cristina; Radice, Paolo; Barile, Monica; Menin, Chiara; D'Andrea, Emma; Montagna, Marco.
In: Journal of Clinical Oncology, Vol. 26, No. 1, 01.01.2008, p. 26-31.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy
AU - Malacrida, Sandro
AU - Agata, Simona
AU - Callegaro, Monia
AU - Casella, Cinzia
AU - Barana, Daniela
AU - Scaini, Maria C.
AU - Manoukian, Siranoush
AU - Oliani, Cristina
AU - Radice, Paolo
AU - Barile, Monica
AU - Menin, Chiara
AU - D'Andrea, Emma
AU - Montagna, Marco
PY - 2008/1/1
Y1 - 2008/1/1
N2 - Purpose: A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population. Patients and Methods: Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del. Results: We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message. Conclusion: We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
AB - Purpose: A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population. Patients and Methods: Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del. Results: We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message. Conclusion: We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
UR - http://www.scopus.com/inward/record.url?scp=37849010906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37849010906&partnerID=8YFLogxK
U2 - 10.1200/JCO.2007.13.2118
DO - 10.1200/JCO.2007.13.2118
M3 - Article
C2 - 18165637
AN - SCOPUS:37849010906
VL - 26
SP - 26
EP - 31
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 1
ER -