ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2269del (p.Val757fs) (rs80357583)

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Total submissions: 11
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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) RCV000031040 SCV000282276 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000215693 SCV000275788 pathogenic Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031040 SCV000325310 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000486157 SCV000568420 pathogenic not provided 2018-11-14 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.2269delG at the cDNA level and p.Val757PhefsX8 (V757FfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAGG[delG]TTTTG. The deletion causes a frameshift which changes a Valine to a Phenylalanine at codon 757, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2269delG, also published as 2388delG using alternate nomenclature, has been reported in patients with personal and/or family histories of breast and ovarian cancer (Stoppa-Lyonnet 1997, Rashid 2006, Ramus 2007, Stegel 2011, Kang 2015, Minucci 2015, Kwong 2016). We consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769719 SCV000901139 pathogenic Breast and/or ovarian cancer 2017-10-24 criteria provided, single submitter clinical testing
Color RCV000215693 SCV000911348 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496582 SCV001360676 pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2269delG (p.Val757PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. c.2269delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kowalick_2018, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031040 SCV000053634 pathogenic Breast-ovarian cancer, familial 1 2009-12-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031040 SCV000144362 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496582 SCV000587204 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000486157 SCV000778760 pathogenic not provided 2017-03-29 no assertion criteria provided clinical testing

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