BRCA1 and BRCA2 mutations in Scotland and Northern Ireland

Abstract

BRCA1 and BRCA2 mutations have been identified in 107 families in Scotland and Northern Ireland. Ninety-seven of these families had been referred to regional cancer genetics centres and a further 10 were identified from a sequential series of male breast cancers treated in Edinburgh. Fifty-nine of the families had a mutation in BRCA1 and 46 in BRCA2. Two families had both. Family trees were extended and cancer diagnoses verified by means of the unusually complete and accessible Scottish and Northern Irish records. Ten specific recurring mutations (five in each gene) accounted for almost half of the total detected, and almost one-quarter were accounted for by just two (BRCA1 2800 delAA and BRCA2 6503 delTT). The prevalence of breast cancer is similar for BRCA1 and BRCA2 mutation families (average 3.7 and 3.6 per family), but the former have a much greater risk of ovarian cancer (average 1.5 and 0.6 per family, respectively). For breast cancer, age of onset tended to be younger in BRCA1 mutation carriers but, for ovarian cancer, there was no difference between BRCA1 and BRCA2 families in mean age at diagnosis. Mutations within the 5 0 two-thirds of BRCA1 carry a significantly higher relative risk of ovarian cancer and the same is true for mutations within the central portion of BRCA2 (the 'OCCR'). In the former case, this appears to be because of differences in absolute risk for both ovarian and breast cancer, while, in the latter, only ovarian cancer risk varies significantly. The findings confirm that founder mutations are present within the Scottish/ Northern Irish population and have implications for the organisation of molecular screening services.

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

“…A very low frequency of BRCA1 heterozygote population could potentially explain our findings, though this cannot be verified in the absence of the frequency of BRCA1/2 mutation in Irish population. Two publications had reported a relatively higher BRCA2 : BRCA1 mutation ratio [ 34 , 35 ], including a 2.7:1 ratio of BRCA2 : BRCA1 mutations amongst 120 patients with non-mucinous OC undergoing routine BRCA1/2 germline mutation testing. Interestingly, the reports originate from Scotland/Northern Ireland and West Scotland.…”

A Comprehensive Focus on Global Spectrum ofBRCA1andBRCA2Mutations in Breast Cancer

“…The Scottish and Irish BC patients were carriers of two Ashkenazi Jews founder mutations, 185 delAG and 5382 insC which include the most frequent BRCA1 and BRCA2 mutations, respectively. Interestingly, the 4184 del4 mutation in BRCA1 has been found in BC patients with Welsh, South Thames, Oxford, Yorkshire, Irish, and Scottish origin [ 78 – 80 ].…”

A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer

“… 899 AA short [ 158 ] p.Arg2520Ter 4-4A BRCA2 25 of 27 c.9294C > G a rs80359200 3 d ; Pathogenic e ; Familial breast and breast-ovarian cancer f . 321 AA short [ 159 ] p.Tyr3098Ter 7-3A PALB2 4 of 13 c.1240C > T a rs180177100 3 d ; Pathogenic e ; Familial breast cancer, Hereditary cancer-predisposing syndrome f . 773 AA short [ 58 ] p.Arg414Ter 4-4D PALB2 4 of 13 c.1042C > T a Novel - 839 AA short - p.Gln348Ter a Confirmed by Sanger sequencing b Not confirmed by Sanger sequencing c If available d Number of submissions e Clinical significance f Condition(s) …”

“…As a consequence, functional domains of PALB2 that interact with BRCA1, RAD51, BRCA2, and POLH are lost [ 137 ]. Two known nonsense mutations were found in BRCA2 , c.7558C > T in exon 15 [ 158 ] and c.9294C > G in exon 25 [ 159 ]. The first (chr13:32930687C > T; rs80358981; 7-1G) causes the loss of the BRCA2 region that binds FANCD2, responsible for loading BRCA2 onto damaged chromatin [ 160 ].…”