ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.670_673dup (p.Thr225fs) (rs730881601)

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Total submissions: 3
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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) RCV000241290 SCV000300343 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160264 SCV000210705 pathogenic Familial cancer of breast 2014-06-24 criteria provided, single submitter clinical testing This variant is denoted as BRCA2 c.673_674insGATA (aka c.670_673dupGATA) at the cDNA level and p.Thr225ArgfsX5 (T225RfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is TCAT{GATA}CTAC. The duplication causes a frameshift, which changes a Threonine to an Arginine at codon 225 in exon 8, and creates a premature stop codon at position 5 of the new reading frame. Although this mutation has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.670_673dupGATA, also known as c.898_901dupGATA using alternate nomenclature, is considered to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC), an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. Breast and ovarian cancer are the predominant BRCA2-related cancers that unaffected female mutation carriers are at risk to develop. The lifetime risk for breast cancer is estimated to be 41 to 84% and the lifetime risk for ovarian cancer is estimated to be 11 to 27% (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). Graeser et al. (2009) found that women who harbor a pathogenic BRCA2 mutation have an increased risk for contralateral breast cancer that is dependent on age at initial diagnosis. It is estimated that the risk to develop a second breast cancer within 10 years of the first diagnosis if initially diagnosed less than age 40 years of age is 21%, between the ages of 40 and 50 is 13% and after the age of 50 is 9%. Additionally, it is estimated that the risk to develop a second breast cancer within 25 years of their first diagnosis if initially diagnosed less than age 40 years of age is 63%, between the ages of 40 and 50 is 49% and after the age of 50 is 17%. 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). BRCA2 mutations have also been associated with an increased risk for cutaneous malignant melanoma (Liede 2004, The Breast Cancer Linkage Consortium 1999). The variant is found in HEREDICANCER panel(s).
GeneDx RCV000486203 SCV000564759 pathogenic not provided 2015-02-16 criteria provided, single submitter clinical testing This duplication of 4 nucleotides is denoted BRCA2 c.670_673dupGATA at the cDNA level and p.Thr225ArgfsX5 (T225RfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is TCAT[GATA]CTAC. The duplication causes a frameshift, which changes a Threonine to an Arginine at codon 225, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.670_673dupGATA, also known as c.898_901dupGATA using alternate nomenclature, is considered to be pathogenic.

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