The occurrence of germline BRCA1 and BRCA2sequence alterations in Slovenian population

Abstract

BackgroundThe BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer.MethodsThe BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing.ResultsEighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1.ConclusionAmong the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families).

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

“…c.843_846delCTCA and c.1687C > T were both detected in Slovenia (Stegel et al, 2011), Italy (Santarosa et al, 1998), Austria (Wagner et al, 1998), Germany (Meindl and German Consortium for Hereditary Breast and Ovarian Cancer, 2002), Czech Republic (Machackova et al, 2008) and Slovakia (Konecny et al, 2011), while Switzerland reported only c.1687C > T (Schoumacher et al, 2001). BRCA1 c.5251C > T was found in Slovenia (Stegel et al, 2011), Austria (Wagner et al, 1998), Germany (Meindl and German Consortium for Hereditary Breast and Ovarian Cancer, 2002), Poland (Gorski et al, 2004) and Greece (Konstantopoulou et al, 2008). BRCA1 c.676delT was detected in Poland (Gorski et al, 2004) and Germany (Dong et al, 1998) and BRCA2 c.9371A> T was detected in Poland (Kozlowski and Krzyzosiak, 2001) and in Slovenia as an UV (Stegel et al, 2011).…”

“…Accordingly, they were detected in most of the Slavic countries (Slovenia (Stegel et al, 2011), Serbia (Brankovic-Magic, 2006, Czech Republic (Machackova et al, 2008), Slovakia (Konecny et al, 2011) and Poland (Gorski et al, 2004)). Screening in Ukraine and Bulgaria is still incomplete but there is record of Canadians of Table 5 BRCA2 sequence variants detected in Croatian candidates.…”

“…Although some authors (Kwiatkowska et al, 2001;Stegel et al, 2011) consider BRCA2 nonsense mutation c.9371A > T (Asn3124Ile) as an UV, our in silico analysis agreed with its previously predicted (Karchin et al, 2008;Rajasekaran et al, 2008). Since the Asn3124Ile substitution is located at highly conserved protein position in the OB3 domain, one of the oligonucleotide ssDNA-binding fold motifs, the aminoacid change from hydrophilic and negatively charged asparagine to hydrophobic isoleucine should be interpreted as a missense mutation affecting the BRCA2 role in the repair of double-strand DNA breaks by homologous recombination (Holloman, 2011;Yang et al, 2002).…”

“…BRCA1 c.1252G>T and BRCA2 c.6641dupC to our knowledge have not been detected in nearby countries. BRCA2 mutation c.6491_6494del4 was detected in the Slovenian population (Stegel et al, 2011).…”

Pedigree and BRCA gene analysis in breast cancer patients to identify hereditary breast and ovarian cancer syndrome to prevent morbidity and mortality of disease in Indian population

“…This was also previously described as a polymorphism, rs28897710, in Slovenian population. 32 The second VUS was c.5986G>A (p.Ala1996Thr) in exon 11, which has been previously described as a harmful variant in a Croatian BC study 33 and is reported in ClinVar five times in HBOCS patients, with conflicting interpretation of pathogenicity. The third one was c.7445C>T (p.Thr2482Ile) in exon 15.…”