ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5173_5176GAAA[1] (p.Arg1726fs) (rs80357867)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000048843 SCV000883465 pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131829 SCV000186884 pathogenic Hereditary cancer-predisposing syndrome 2017-09-28 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)
Breast Cancer Information Core (BIC) (BRCA1) RCV000031225 SCV000145373 pathogenic Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031225 SCV000326194 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031225 SCV000785673 pathogenic Breast-ovarian cancer, familial 1 2017-10-27 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031225 SCV000300220 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000048843 SCV000210055 pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5177_5180delGAAA at the cDNA level and p.Arg1726LysfsX3 (R1726KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAA[delGAAA]AATG. The deletion causes a frameshift, which changes an Arginine to a Lysine at codon 1726, and creates a premature stop codon at position 3 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.5177_5180delGAAA, previously reported as BRCA1 5296del4 using alternate nomenclature, has been observed in several individuals and families with breast and ovarian cancer (Gao 1997, Tai 2007, Song 2014, Pal 2015, Ewald 2016). Based on current information, we consider this variant to be pathogenic.
GeneKor MSA RCV000048843 SCV000693544 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785209 SCV000923777 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000167855 SCV000918736 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5177_5180delGAAA (p.Arg1726LysfsX3) 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 (e.g., p.Met1728fsX2 and p.Gln1747X). The variant allele was found at a frequency of 8e-06 in 250304 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-06 vs 0.001), allowing no conclusion about variant significance. The c.5177_5180delGAAA variant has been reported in the literature in numerous individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to 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.
Invitae RCV000167855 SCV000076856 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1726Lysfs*3) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357975, ExAC 0.01%). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 9150171, 22923021, 23397983, 24504028, 26287763, 27831900). This variant is also known as 5296del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37644). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000167855 SCV000605751 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-28 criteria provided, single submitter clinical testing The p.Arg1726fs variant in BRCA1 has been reported in >30 individuals with BRCA1 -associated cancers (Gao 1997, Cunningham 2014, Stegel 2011, Trujillano 2015, Br east Cancer Information Core (BIC) database). It has also been identified in 1/1 0314 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org,; dbSNP rs80357975). This variant is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 17 26 and leads to a premature termination codon 3 amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hered itary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000300220.2). In summary, this variant meets our criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048843 SCV000296306 pathogenic not provided 2015-03-11 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167855 SCV000587473 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031225 SCV000053825 pathogenic Breast-ovarian cancer, familial 1 2013-05-28 no assertion criteria provided clinical testing

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