PURPOSE: Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan. MATERIALS AND METHODS: PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations. RESULTS: A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127, 0.8%). Besides, four in silico-predicted potentially functional mutations including three missense mutations and one 5' untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (≤ 30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated. CONCLUSION: Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan.
5' Untranslated Regions ; Breast Neoplasms ; Chromatography, Liquid ; Codon, Nonsense ; Computer Simulation ; DNA Repair ; Germ-Line Mutation ; Humans ; Mass Screening ; Mutation, Missense ; Pakistan ; Prevalence ; Sequence Analysis, DNA

In the context of ARVC, a systematic review of the validation of the ARVC risk score can provide insights into the accuracy and reliability of this score in identifying patients at high risk of ARVC. Digital databases were searched to identify the relevant studies using Medical Subject Headings (MeSH). A total of 8 studies were included in this systematic review. A total of 8 studies were included in this review. The review found that the sensitivity of the ARVC risk scores ranged from 80 to 95%, and the specificity ranged from 31 to 79%. The PPV was 55%, and the NPV was 88%. The ARVC score provided a C-index for a 5-year VA risk prediction of 0.84 [95% CI (0.74–0.93)] and a Harrell C-index of 0.70 (95% CI 0.65–0.75). The calibration slope was 1.01 (95% CI 0.99–1.03). ARVC score demonstrated a significant event 5-year threshold between 15 and 20% and the classical ARVC 5-years/freedom-from-VA rate was 0.76(0.66–0.89) and the non-classical form 5-years/freedom-from-VA rate was 0.58 (0.43–0.78). In conclusion, the validation of ARVC risk scores is an essential step toward improving the accuracy of ARVC diagnosis and risk stratification. Further studies are needed to establish the accuracy and reliability of ARVC risk scores and to address the limitations of the current evidence.