ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3195_3198del (p.Asn1066fs) (rs80359375)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113145 SCV000300601 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000456127 SCV000072156 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1066Leufs*10) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16949048, 17100994, 26187060, 17333343, 26306726). This variant is also known as 3423delTAAT (1075X) and as c.3192_3195delAATT in the literature. ClinVar contains an entry for this variant (Variation ID: 51419). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000044143 SCV000210735 pathogenic Familial cancer of breast 2013-11-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3195_3198delTAAT at the cDNA level and p.Asn1066LeufsX10 (N1066LfsX10) at the protein level. The normal sequence with the bases that are deleted in braces is: CAAT{TAAT}ACTG. The deletion causes a frameshift, changing an Asparagine to a Leucine at codon 1066, and creating a premature stop codon at position 10 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. BRCA2 c.3195_3198delTAAT, also known as 3423del4 or 3423delTAAT using alternative nomenclature, has been reported in association with breast cancer (Kim 2006) and is listed as clinically important in the Breast Cancer Information Core (BIC) database 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). The variant is found in BRCA1-BRCA2 panel(s).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113145 SCV000326832 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000510021 SCV000608011 pathogenic Hereditary cancer-predisposing syndrome 2017-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000456127 SCV000694674 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-17 criteria provided, single submitter clinical testing Variant summary: The c.3195_3198delTAAT (p.Asn1066Leufs) variant in BRCA2 gene is a frameshift change that results in the loss of the 2344 amino acids of protein (~61%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (119892 and 242068 chrs tested, respectively). The c.3195_3198delTAAT has been reported in multiple affected individuals via published reports and cited as pathogenic by several reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Color RCV000510021 SCV000905008 pathogenic Hereditary cancer-predisposing syndrome 2017-12-11 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113145 SCV000146187 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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