Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Caputo, Sandrine M.; Golmard, Lisa; Léoné, Mélanie; Damiola, Francesca; Guillaud‐Bataille, Marine; Révillion, Françoise; Rouleau, Etienne; Derive, Nicolas; Buisson, Adrien; Basset, Noémie; Schwartz, Mathias; Vilquin, Paul; Garrec, Céline; Privat, Maud; Gay‐Bellile, Mathilde; Abadie, Caroline; Abidallah, Khadija; Airaud, Fabrice; Allary, Anne-Sophie; Barouk-Simonet, Emmanuelle; Belotti, Muriel; Benigni, Charlotte; Benusiglio, Patrick R.; Berthemin, Christelle; Berthet, Pascaline; Bertrand, Ophelie; Bézieau, Stéphane; Bidart, Marie; Bignon, Yves‐Jean; Birot, Anne-Marie; Blanluet, Maud; Bloucard, Amelie; Bombled, Johny; Bonadona, Valérie; Bonnet, Françoise; Bonnet-Dupeyron, Marie-Noëlle; Boulaire, Manon; Boulouard, Flavie; Bouras, Ahmed Fouad; Bourdon, Violaine; Brahimi, Afane; Brayotel, Fanny; Paillerets, B. Bressac de; Bronnec, Noémie; Bubien, Virginie; Bruno, Benedetto; Cabaret, Odile; Carriere, Jennifer; Chiésa, Jean; Chieze-Valéro, Stephanie; Cohen, C.; Cohen-Haguenauer, Odile; Colas, Chrystelle; Collonge‐Rame, Marie‐Agnès; Conoy, Anne-Laure; Coulet, Florence; Coupier, Isabelle; Crivelli, Louise; Cusin, Véronica; Pauw, Antoine de; Dehainault, Catherine; Delhomelle, Hélène; Delnatte, Capucine; Demontety, Sophie; Denizeau, Philippe; Devulder, Pierre; Dreyfus, Hélène; d’Enghein, Catherine Dubois; Dupré, Anaïs; Durlach, A.; Dussart, Sophie; Fajac, Anne; Fekairi, Samira; Fert‐Ferrer, Sandra; Fiévet, Alice; Fouillet, Robin; Mouret-Fourme, Emmanuelle; Gauthier‐Villars, Marion; Gesta, Paul; Giraud, Sophie; Gladieff, Laurence; Goldbarg, Veronica; Goussot, Vincent; Guibert, Virginie; Guillerm, Erell; Guy, Christophe; Hardouin, Agnès; Heude, Céline; Houdayer, Claude; Ingster, Olivier; Jacquot-Sawka, Caroline; Jones, Natalie; Krieger, Sophie; Lacoste, Sofiane; Lallaoui, Hakima; Larbre, Hélène; Laugé, Anthony; Guyadec, Gabrielle Le; Mentec, Marine Le; Lecerf, Caroline; Gall, Jessica Le; Legendre, Bérengère; Legrand, Clémentine; Legros, Angélina; Lejeune, Sophie; Lidereau, Rosette; Lignon, Norbert; Limacher, Jean‐Marc; Livon, Doriane; Lizard, Sarab; Longy, Michel; Lortholary, Alain; Macquère, Pierre; Mailliez, Audrey; Malsa, Sarah; Margot, Henri; Mari, Véronique; Maugard, Christine M.; Meira, Cindy; Menjard, Julie; Molière, Diane; Moncoutier, Virginie; Moretta-Serra, Jessica; Müller, Etienne; Nevière, Zoé; Tuan, Thien-vu Nguyen Minh; Noguchi, Tetsuro; Noguès, Catherine; Oca, Florine; Popovici, Cornel; Prieur, Fabienne; Raad, Sabine; Rey, Jean-Marc; Ricou, Agathe; Salle, Lucie; Saule, Claire; Sévenet, Nicolas; Simaga, F; Sobol, Hagay; Suybeng, Voreak; Tennevet, Isabelle; Tenreiro, Henrique; Tinat, Julie; Toulas, Christine; Turbiez, Isabelle; Uhrhammer, Nancy; Perre, P Vande; Vaur, Dominique; Venat, Laurence; Viellard, Nicolas; Villy, Marie‐Charlotte; Warcoin, Mathilde; Yvard, Alice; Zattara, Hélène; Caron, Olivier; Lasset, Christine; Remenieras, Audrey; Boutry‐Kryza, Nadia; Castéra, Laurent; Stoppa‐Lyonnet, Dominique

doi:10.1016/j.ajhg.2021.09.003

Cited by 21 publications

(16 citation statements)

References 67 publications

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“…Interestingly, our model predicted the variant W31S located in the PALB2-binding domain of BRCA2 as pathogenic, which is consistent with a recent study finding 33 . The tryptophan residue at position 31 of BRCA2 is one of the essential residues for BRCA2 interaction with PALB2, as it is known to create a polar bridge with Ser1065 of PALB2 34 .…”

Section: Resultssupporting

confidence: 92%

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Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2

Al‐Jarf

Shen

Pires

et al. 2022

Sci Rep

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BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanism. DNA repair defects caused by BRCA1 and BRCA2 missense variants increase the risk of developing breast and ovarian cancers. Accurate identification of these variants becomes clinically relevant, as means to guide personalized patient management and early detection. Next-generation sequencing efforts have significantly increased data availability but also the discovery of variants of uncertain significance that need interpretation. Experimental approaches used to measure the molecular consequences of these variants, however, are usually costly and time-consuming. Therefore, computational tools have emerged as faster alternatives for assisting in the interpretation of the clinical significance of newly discovered variants. To better understand and predict variant pathogenicity in BRCA1 and BRCA2, various machine learning algorithms have been proposed, however presented limited performance. Here we present BRCA1 and BRCA2 gene-specific models and a generic model for quantifying the functional impacts of single-point missense variants in these genes. Across tenfold cross-validation, our final models achieved a Matthew's Correlation Coefficient (MCC) of up to 0.98 and comparable performance of up to 0.89 across independent, non-redundant blind tests, outperforming alternative approaches. We believe our predictive tool will be a valuable resource for providing insights into understanding and interpreting the functional consequences of missense variants in these genes and as a tool for guiding the interpretation of newly discovered variants and prioritizing mutations for experimental validation.

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Section: Resultssupporting

confidence: 92%

“…We observed many dissimilarities between our final model prediction and the InterVar tool ACMG/AMP variants scoring. This observance is in line with a recent study 33 that revealed distinctions between their classification established on a multifactorial model and ACMG/AMP scoring.…”

Section: Resultssupporting

confidence: 91%

Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2

Al‐Jarf

Shen

Pires

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In the case of D1733G and V1687G, a deeper analysis of WES data would be of interest, as VUSs might be found in other breast-cancer-related genes, thus explaining these discrepant results. Thus, likewise genetic testing alone is unsatisfactory for the classification of BRCA1 VUSs, functional assays appear also insufficient regardless of the cellular model used: establishing a reliable classification of variants will only be possible by integrating data from multiple sources such as family history, gene and protein structure and functional assays [ 52 , 58 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance

et al. 2021

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Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

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“…[182][183][184]187 In particular, most reclassified VUS (eg, >90% 184,187 ) are downgraded to likely benign or benign. [182][183][184][185][187][188][189] Strategies to generate evidence to reclassify VUS include family segregation studies, 190,191 functional studies, 192,193 and data sharing. 194,195 Variant reclassifications can affect patients' medical care.…”

Section: Interpretation Of Genetic Findingsmentioning

confidence: 99%

“…It has been consistently observed that most reclassified variants are downgraded to a more benign classification 182–184,187 . In particular, most reclassified VUS (eg, >90% 184,187 ) are downgraded to likely benign or benign 182–185,187–189 . Strategies to generate evidence to reclassify VUS include family segregation studies, 190,191 functional studies, 192,193 and data sharing 194,195 .…”

Section: Interpretation Of Genetic Findingsmentioning

confidence: 99%

Principles of molecular testing for hereditary cancer

Mighton

Lerner‐Ellis

2022

Genes Chromosomes & Cancer

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Molecular testing for hereditary cancers has rapidly advanced over the past two decades. Next-generation sequencing has been widely adopted, which has made molecular testing increasingly accessible, and large gene panels are now routinely used in clinical care. Effectively using molecular testing as a tool for the management of patients with hereditary cancer involves understanding various basic principles. In this article, we provide an overview of general principles for molecular germline testing for hereditary cancer syndromes. We overview hereditary cancer etiology, clinical indications for molecular testing, test methodologies and limitations, interpretation and reporting of test results, the evolving nature of evidence on gene-disease relationships and penetrance, and resources related to the clinical management of hereditary cancer syndromes.

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Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Cited by 21 publications

References 67 publications

Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2

Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2

Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance

Principles of molecular testing for hereditary cancer

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