International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

Abstract

The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,440 suspected HBOC families from 22 labs from 13 countries from several continents. Whereas the c.156_157insAluBRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all having in common the fact that they are relatively recent immigrants of Portuguese origin in those countries. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation has occurred 558±215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript with exon 3 skipping in c.156_157insAlu BRCA2 mutation carriers and in controls, indicating that disruption of alternative transcript ratios is the mechanism causing hereditary breast/ovarian cancer associated with this BRCA2 rearrangement. We further show that the cumulative incidence of breast cancer in c.156_157insAlu BRCA2 mutation carriers does not differ from that of other BRCA2 and BRCA1 pathogenic mutations, further strengthening its role as the major contributor to hereditary predisposition to breast cancer in Portugal. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement, ideally prior to screening of the entire coding regions of BRCA1 and BRCA2.3

Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

“…Similarly, the detection of complete in-frame skipping of exon 3 from the mutant allele for BRCA2 c.316?5G[A is comparable to findings from Bonnet et al [16] for c.316?5G[C, and our study demonstrates the importance of quantifying the contribution of the variant allele to aberrant and variant transcripts when a variant is associated with upregulation of the naturally occurring delta exon 3 isoform identified in healthy controls. Further studies may help clarify the debate regarding the clinical significance of variants reported to result in exon 3 skipping [23,24,[28][29][30][31].…”

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines

“…The clinical presentation of HBOC among Hispanic subpopulations is very similar to non-Hispanic cohorts [12, 17, 19, 21, 25, 36–40]. Most studies reported that the majority of women that met inclusion criteria had BC diagnosed before age 50 (67.5%; range: 50.4–81.4%).…”

“…The BRCA2 c.3922G > T mutation has only been identified in the Puerto Rican cohort, and in US Hispanic studies that include Puerto Ricans and not in other Latin American countries [26]. In Portugal, the BRCA2 c.156_157insAlu mutation seen in families of Portuguese descent was also identified as a founder mutation that occurred around 558 years ago [31, 32, 36]. Moreover, the BRCA1 c.5266dup mutation was identified as a founder Brazilian mutation of Eastern European origin [37].…”

“…Additionally, family history of BC was found on an average of 16.1% (range: 5.2–27%) of Hispanic women recruited in the studies described in this review. Comparisons of the age at BC diagnosis among the Hispanic subpopulations described above showed that Caribbean Hispanics (Bahamas, Puerto Rico and Cuba) were diagnosed at later ages (mean: 45.9 years; range: 40–51.8 years) than their South American (mean: 44 years), Central American (mean: 41.6 years) and US Hispanic (mean: 38.5 years) counterparts [17, 19, 21, 25, 28–30, 32, 36–41]. …”

Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada

“…Finally, the third variant, c.3287A > G (p.N1096S), was identified in a proband diagnosed with bilateral breast cancer from a Portuguese family (Additional file 1: Figure S2C). Given the previously reported existence of a Portuguese founder mutation in BRCA2 [20], we considered the possibility that this novel PALB2 variant was a founder mutation and subsequently analyzed for its presence in a larger Portuguese series. The c.3287A > G (p.N1096S) variant was not observed in an additional 311 Caucasian index cases primarily from Northern Portugal who were negative for BRCA1 and BRCA2 mutations.…”