ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1953_1956delGAAA (p.Lys653Serfs) (rs80357526)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131893 SCV000186948 pathogenic Hereditary cancer-predisposing syndrome 2018-03-22 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)
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000031016 SCV000584016 pathogenic Breast-ovarian cancer, familial 1 2017-07-12 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031016 SCV000144258 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131893 SCV000683003 pathogenic Hereditary cancer-predisposing syndrome 2016-05-16 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031016 SCV000325196 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031016 SCV000677639 pathogenic Breast-ovarian cancer, familial 1 2016-11-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000203663 SCV000591356 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031016 SCV000282268 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735495 SCV000863633 pathogenic Breast and/or ovarian cancer 2009-03-23 no assertion criteria provided clinical testing
GeneDx RCV000047653 SCV000210017 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing This deletion of four nucleotides is denoted BRCA1 c.1953_1956delGAAA at the cDNA level and p.Lys653SerfsX47 (K653SfsX47) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAA[delGAAA]AAAAAG. The deletion causes a frameshift, which changes a Lysine to a Serine at codon 653, and creates a premature stop codon at position 47 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.1953_1956delGAAA, also known as BRCA1 2072_2075delGAAA, BRCA1 2072delGAAA, and BRCA1 2072del4 using alternate nomenclature, has been reported in multiple individuals with breast and/or ovarian cancer (van Orsouw 1999, Risch 2006, Lee 2008, Esteban Carde?osa 2010, Zhang 2011, de Juan Jimenez 2013, Konstantopoulou 2014, Nabholtz 2014, Lerner-Ellis 2017). We consider this variant to be pathogenic.
GeneKor MSA RCV000047653 SCV000693513 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000031016 SCV000593684 pathogenic Breast-ovarian cancer, familial 1 2016-02-29 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785401 SCV000923973 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000203663 SCV000918774 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-28 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1953_1956delGAAA (p.Lys653SerfsX47) 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 (eg. c.1960A>T/p.Lys654X and c.1961delA/p.Lys654fsX47). The variant was absent in 276832 control chromosomes (gnomAD). The variant, c.1953_1956delGAAA, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (vanOrsouw_1999, Ciernikova_2005, Risch_2006, Konstantopoulou_2014, Feliubadalo_2017). 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. 11 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 RCV000203663 SCV000075666 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys653Serfs*47) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 10528853, 22434525, 23479189, 24827135). This variant is also known as 2072delGAAA and 2072del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37435). 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 RCV000203663 SCV000605752 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Lys653fs variant in BRCA1 has been reported in >30 individuals with BRCA1- associated cancers (Caux-Montcoutier 2011, Fostira 2011, Juan Jimenez 2013, Kons tantopoulou 2014, Nabholtz 2014, van Oursouw 1999, Breast Cancer Information Cor e (BIC) database). This variant was also absent from large population studies, t hough the ability of these studies to accurately detect indels may be limited. T his variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 653 and leads to a premature termination co don 47 amino acids downstream. This alteration is then predicted to lead to a tr uncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282268.1). I n summary, this variant meets criteria to be classified as pathogenic for HBOC i n an autosomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047653 SCV000888857 pathogenic not provided 2017-12-02 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000203663 SCV000587173 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031016 SCV000053609 pathogenic Breast-ovarian cancer, familial 1 2012-08-20 no assertion criteria provided clinical testing

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