IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22–1.74; P = 2 × 10−6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01–1.78; P = .04), and c. 5261 to c.5563 (BCCR23, RHR = 1.38; 95% CI, 1.22–1.55; P = 6 × 10−9). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56–0.70; P = 9 × 10−17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06–2.78; P = .03), c.772 to c.1806 (BCCR13; RHR = 1.63; 95% CI, 1.10–2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69–3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44–0.60; P = 6 × 10−17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41–0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

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Objective Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) remains one of the most frequently missed congenital anomalies prenatally. The aim of our study was to elucidate the sonographic manifestation of EA/TEF throughout pregnancy. Methods This was a retrospective study of data obtained from a tertiary center over a 12‐year period. The prenatal ultrasound scans of fetuses with EA/TEF were assessed to determine the presence and timing of detection of three principal signs: small/absent stomach and worsening polyhydramnios, both of which were considered as ‘suspected’ EA/TEF, and esophageal pouch, which was considered as ‘detected’ EA/TEF. We assessed the yield of the early (14–16 weeks' gestation), routine mid‐trimester (19–26 weeks) and third‐trimester (≥ 27 weeks) anomaly scans in the prenatal diagnosis of EA/TEF. Results Seventy‐five cases of EA/TEF with available ultrasound images were included in the study. A small/absent stomach was detected on the early anomaly scan in 3.6% of fetuses scanned, without a definitive diagnosis. On the mid‐trimester scan, 19.4% of scanned cases were suspected and 4.3% were detected. On the third‐trimester anomaly scan, 43.9% of scanned cases were suspected and 33.9% were detected. An additional case with an esophageal pouch was detected on magnetic resonance imaging (MRI) in the mid‐trimester and a further two were detected on MRI in the third trimester. In total, 44.0% of cases of EA/TEF in our cohort were suspected, 33.3% were detected and 10.7% were suspected but, eventually, not detected prenatally. Conclusions Prenatal diagnosis of EA/TEF on ultrasound is not feasible before the late second trimester. A small/absent stomach may be visualized as early as 15 weeks' gestation. Polyhydramnios does not develop before the mid‐trimester. An esophageal pouch can be detected as early as 22 weeks on a targeted scan in suspected cases. The detection rates of all three signs increase with advancing pregnancy, peaking in the third trimester. The early and mid‐trimester anomaly scans perform poorly as a screening and diagnostic test for EA/TEF. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.