Universität zu Köln

Tudini, Emma, Moghadasi, Setareh, Parsons, Michael T., van der Kolk, Lizet, van den Ouweland, Ans M. W., Niederacher, Dieter, Feliubadalo, Lidia ORCID: 0000-0002-1736-0112, Wappenschmidt, Barbara, Spurdle, Amanda B. and Lazaro, Conxi (2018). Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G > T p.(Gly1770Val). Breast Cancer Res. Treat., 172 (2). S. 497 - 504. NEW YORK: SPRINGER. ISSN 1573-7217

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Abstract

PurposeClassification of rare BRCA1 missense variants presents a major challenge for the counseling and treatment of patients. Variant classification can be complicated by conflicting lines of evidence. BRCA1 c.5309G>T p.(Gly1770Val) has been shown to abrogate BRCA1 protein homologous DNA repair; however, multiple sequence alignment demonstrates a lack of sequence conservation at this position, suggesting that glycine at position 1770 may not be essential for cellular maintenance in humans. We analyzed clinical information to resolve the classification of BRCA1 c.5309G>T p.(Gly1770Val).MethodsWe performed multifactorial likelihood analysis combining segregation data for 14 informative families, and breast tumor histopathological data for 17 variant carriers, ascertained through the ENIGMA consortium.ResultsBayes segregation analysis gave a likelihood ratio of 101:1 in favor of pathogenicity. The vast majority of breast tumors showed features indicative of pathogenic variant carrier status, resulting in a likelihood ratio of 15800794:1 towards pathogenicity. Despite a low prior probability of pathogenicity (0.03) based on bioinformatic prediction, multifactorial likelihood analysis including segregation and histopathology analysis gave a posterior probability of >0.99 and final classification of Pathogenic.ConclusionsWe provide evidence that BRCA1 c.5309G>T p.(Gly1770Val), previously described as a Moroccan founder variant, should be treated as a disease-causing variant despite a lack of evolutionary conservation at this amino acid position. Additionally, we stress that bioinformatic information should be used in combination with other data, either direct clinical evidence or some form of clinical calibration, to arrive at a final clinical classification.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tudini, Emma UNSPECIFIED UNSPECIFIED UNSPECIFIED Moghadasi, Setareh UNSPECIFIED UNSPECIFIED UNSPECIFIED Parsons, Michael T. UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Kolk, Lizet UNSPECIFIED UNSPECIFIED UNSPECIFIED van den Ouweland, Ans M. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederacher, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Feliubadalo, Lidia UNSPECIFIED orcid.org/0000-0002-1736-0112 UNSPECIFIED Wappenschmidt, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Spurdle, Amanda B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lazaro, Conxi UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168532
DOI:	10.1007/s10549-018-4903-y
Journal or Publication Title:	Breast Cancer Res. Treat.
Volume:	172
Number:	2
Page Range:	S. 497 - 504
Date:	2018
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1573-7217
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UNCERTAIN SIGNIFICANCE; OVARIAN-CANCER; SEQUENCE VARIANTS; CLASSIFICATION; BREAST; SUBSTITUTIONS; MUTATIONS; MODEL; ASSAY; RISK Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16853