Abstract
IntroductionUnclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10).MethodsFor co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated.ResultsWe identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 Ă— 10-8 in favour of neutrality of the variant.ConclusionOur data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Highlights
Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene
Besides clear pathogenic mutations, many unclassified variants exist, for example, missense mutations of unknown relevance that constitute about 30% of all mutations detectable in the BRCA1 or BRCA2 genes [1,2]
We have investigated the common variant S384F (BRCA2, exon 10) in a large kindred (BN326) using these approaches
Summary
Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. We have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). Besides clear pathogenic mutations (nonsense mutations or insertions and deletions leading to truncated proteins), many unclassified variants exist, for example, missense mutations of unknown relevance that constitute about 30% of all mutations detectable in the BRCA1 or BRCA2 genes [1,2]. A lack of functional assays has hampered the conclusive validation of the consequences of these variants. This raises various problems for the clinical management, genetic counselling and personal life planning of people who carry such an unclassified BRCA1/2 variant. We have investigated the common variant S384F (BRCA2, exon 10) in a large kindred (BN326) using these approaches
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
