Are women with pathogenic variants in PMS2 and MSH6 really at high lifetime risk of breast cancer?

We read with some concern the recent article in Genetics in Medicine reporting a high lifetime risk of breast cancer in pathogenic variant (PV) carriers for PMS2 and MSH6 (ref. 1). Although the reported odds ratios for breast cancer were given as MSH6 (2.11; 95% confidence interval [CI] = 1.56–2.86) and PMS2 (2.92; 95% CI = 2.17–3.92) the cumulative risks to age 60 were given as 31.1% (95% CI, 21.9–40.7) and 37.7% (95% CI, 27.5–47.8) respectively. These are equivalent to UK National Institute for Health and Care Excellence (NICE) defined high lifetime risks. These two analyses are inaccurate given that the risk of breast cancer to the age of 60 years in the UK and United States is 5–6%. Therefore, if the risks from incidence ratios and Kaplan–Meier were equivalent, the odds ratios would be over 6-fold for PMS2 and >5-fold for MSH6

Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk. METHODS: The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach. RESULTS: Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers. CONCLUSION: The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?

PURPOSE: The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. METHODS: We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2. RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1. CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases

A Family with Co-existing SDHB and SDHD Mutations Causing Hereditary Paraganglioma Syndrome

Introduction: We report the co-occurrence of a SDHD and a SDHB mutation in a family with hereditary paraganglioma syndrome.  We compare this finding to simultaneous haploinsufficiency of BRCA1 and BRCA2.Presentation of Case: The 28 year old proband presented as an isolated case in the family with a malignant phaeochromocytoma.  Sequencing and MLPA of SDHD and SDHB were performed.  A SDHD splice site mutation, c.169+5GA, was identified in the proband, his sister and their father.  In addition, a SDHB exon 1 deletion was identified by MLPA in the proband, his sister and their mother.  Both mutations have been described previously and considered to be pathogenic. An appropriate screening programme was instituted for carrier relatives. Conclusions: To our knowledge, this is the first report of two SDH subunit mutations in a single family.  Though there was no family history to suggest inherited disorder, the simultaneous testing of both genes was diagnostic.  The family history is consistent with suggestions that the penetrance of SDHB/SDHD mutations is lower than initially thought

Disease expression in juvenile polyposis syndrome : a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

Purpose Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. Results We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). Conclusion This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.Peer reviewe

The pathology of familial breast cancer: Clinical and genetic counselling implications of breast cancer pathology

Approximately 5% of all breast cancers are due to one of the high-risk breast cancer genes BRCA1 and BRCA2, or possibly to a third or fourth moderate- to high-risk gene(s). A further proportion of cases arise in the presence of a less striking family history, with later average age at onset and lower penetrance: familial breast cancer. Bilaterality is a recognized feature of hereditary breast cancer. Cancers often present at an early age, with the contralateral risk high within 10 years. Proof that bilateral malignancies are separate primaries can be difficult histologically, however, especially within 3 years. The recent finding of specific pathological features related to BRCA1 and, to a lesser extent, BRCA2 mutations means that, in addition to bilaterality and family history, a pathological element can be entered into the risk calculation for the presence of BRCA1/BRCA2 mutations. This will facilitate the targeting of mutation testing to families in which a positive result is most likely, and may subsequently influence the clinical management of these families

Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network.

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership