ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2331_2332dup (p.Gly778fs) (rs431825390)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575312 SCV000665887 pathogenic Hereditary cancer-predisposing syndrome 2016-11-28 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)
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000238952 SCV000783617 pathogenic Breast-ovarian cancer, familial 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000159905 SCV000210021 pathogenic Familial cancer of breast 2014-06-25 criteria provided, single submitter clinical testing This insertion of 2 nucleotides is denoted BRCA1 c.2332_2333insTG (a.k.a c.2331_2332dupTG) at the cDNA level and p.Gly778ValfsX15 (G778VfsX15) at the protein level. The normal sequence, with the bases that are inserted in brackets, is TATG{insTG}GCAC. The insertion causes a frameshift, which changes a Glycine to a Valine at codon 778 in exon 10, and creates a premature stop codon at position 15 of the new reading frame. This mutation is also known as BRCA1 2451insTG using alternate nomenclature. 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. We consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC), an autosomal dominant condition that predisposes to early onset breast cancer, ovarian and fallopian tube cancer, as well as other cancers. Breast and ovarian cancer are the predominant BRCA1-related cancers that unaffected female mutation carriers are at risk to develop. The lifetime risk for breast cancer is estimated to be 57 to 84% and the lifetime risk for ovarian cancer is estimated to be 24 to 54% (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Graeser et al. (2009) found that women who harbor a pathogenic BRCA1 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 31%, between the ages of 40 and 50 is 11% and after the age of 50 is 8%. 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 44% and after the age of 50 is 20%. Other cancer risks associated with a BRCA1 pathogenic variant include approximately a 20% risk for prostate cancer in male carriers (Thompson 2002), a 4% risk for male breast cancer (Liede 2004), and an estimated 1 to 3% risk for pancreatic cancer in both men and women (Brose 2002, Thompson 2002). The variant is found in BRCA panel(s).
GeneDx RCV000486921 SCV000564725 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing This duplication of two nucleotides is denoted BRCA1 c.2331_2332dupTG at the cDNA level and p.Gly778ValfsX15 (G778VfsX15) at the protein level. This variant is also known as BRCA1 2450_2451dupTG or 2451insTG using alternate nomenclature. The normal sequence, with the bases that are duplicated in braces, is ATTA[TG]GCAC. The duplication causes a frameshift, which changes a Glycine to a Valine at codon 778, and creates a premature stop codon at position 15 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. We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238952 SCV000296389 pathogenic Breast-ovarian cancer, familial 1 2015-09-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238952 SCV000115101 pathogenic Breast-ovarian cancer, familial 1 2011-10-17 no assertion criteria provided clinical testing

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