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Hered Cancer Clin Pract. 2014 Aug 28;12(1):19. doi: 10.1186/1897-4287-12-19. eCollection 2014.

Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada.

Author information

1
Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada.
2
Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
3
Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Pathology, McGill University, Montreal, QC, Canada.
4
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
5
Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Medical Genetics, University of Cambridge, Cambridge, UK.
6
Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8 L1 Ottawa, ON, Canada ; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
7
Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada ; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada ; Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada.

Abstract

BACKGROUND:

PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.

METHODS:

The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.

RESULTS:

We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del - major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.

CONCLUSIONS:

PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.

KEYWORDS:

BRCA1 and BRCA2 mutation-negative; Hereditary breast cancer; Melanoma; PALB2; Pancreatic cancer

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