Submissions for variant NM_000059.4(BRCA2):c.1190_1191insTTAG (p.Gln397delinsHisTer)

dbSNP: rs80359266

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112890	SCV000300403	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000160266	SCV000210710	pathogenic	Familial cancer of breast	2014-09-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1189_1190insTTAG at the cDNA level and p.Gln397LeufsX25 (Q397LfsX25) at the protein level. The normal sequence, with the bases that are inserted in brackets, is GTCTC[TTAG]AACT. The insertion causes a frameshift, changing a Glutamine to a Leucine at codon 397, and creating a premature stop codon at position 25 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in at least one individual with familial breast/ovarian cancer (Ruark 2013). and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004).Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one from each parent) in the BRCA2 gene. This condition is characterized by an increased risk for malignancy in children including leukemia and certain solid tumors as well as physical abnormalities and bone marrow failure. The variant is found in BR-OV-HEREDIC,BRCA panel(s).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112890	SCV000145829	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496899	SCV000587583	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research