ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1504_1508del (p.Leu502fs) (rs80357888)

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Total submissions: 19
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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) RCV000030998 SCV000282260 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000210987 SCV000075512 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu502Alafs*2) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357888, ExAC 0.01%). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 9150151, 23479189, 23536787, 20104584, 24372583 26296701). This variant is also known as 1623del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37417). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131841 SCV000186896 pathogenic Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000047499 SCV000210014 pathogenic not provided 2019-01-21 criteria provided, single submitter clinical testing This deletion of 5 nucleotides is denoted BRCA1 c.1504_1508delTTAAA at the cDNA level and p.Leu502AlafsX2 (L502AfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is TAAA[TTAAA]GCGT. The deletion causes a frameshift, which changes a Leucine to an Alanine at codon 502, and creates a premature stop codon at position 2 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.1504_1508delTTAAA, previously reported as 1623del5, has been reported in association with breast and ovarian cancer (Peelen 1997, Konstantopoulou 2000, Ellingson 2015, Laraqui 2015, Riahi 2015). We consider this variant to be pathogenic.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000210987 SCV000267856 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000030998 SCV000296339 pathogenic Breast-ovarian cancer, familial 1 2015-07-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030998 SCV000325084 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000030998 SCV000677638 pathogenic Breast-ovarian cancer, familial 1 2017-05-02 criteria provided, single submitter clinical testing
Color RCV000131841 SCV000682968 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000585713 SCV000693509 pathogenic Familial cancer of breast 2020-01-01 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 502 and the creation of a premature translation stop signal 2 amino acid residues later- p.(Leu502Alafs). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This sequence change has been described in individuals and families affected with breast and/or ovarian cancer (PMID: 23479189, 20104584, 24372583 26296701). This mutation has been described in the mutation database ClinVar (Variation ID: 37417)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000030998 SCV000746295 pathogenic Breast-ovarian cancer, familial 1 2017-12-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000047499 SCV001249213 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000210987 SCV001251954 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000210987 SCV001361736 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1504_1508delTTAAA (p.Leu502AlafsX2) 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. The variant allele was found at a frequency of 1.2e-05 in 251068 control chromosomes. c.1504_1508delTTAAA has been reported in the literature in numerous individuals affected with Hereditary Breast and Ovarian Cancer (Konstantopoulou_2014, Li_2018, Peelen_1997, Zheng_2018). These data indicate that the variant is very likely to be associated with disease. Eleven 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) RCV000030998 SCV000053590 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030998 SCV000144114 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 RCV000210987 SCV000587143 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505582 SCV000599904 other Dysgerminoma 2016-05-01 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001004827 SCV000987229 pathogenic bilateral breast cancer 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The BRCA1 p.Leu502Alafs is a known pathogenic frameshift variant in exon 11 and in the serine-rich domain (A344-507R aa) with limited information, however there's information about the SQ (serine-glutamine rich) cluster, whose phosphorylation is critical for allowing adequate time for completing normal Homologous Recombination Repair (HRR) prior to mitosis and preventing cells from entering G1 prematurely resulting in gross chromosomal aberrations (PMID: 28039444). The deletion causes a frameshift, which changes a Leucine to an Alanine at codon 502, and creates a premature stop codon at position 2 of the new reading frame, and this null variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is also in a mutational hotspot of 32 pathogenic frameshift and nonsense variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.0000119 which is less than the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282260.1) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was seen in a 40 years old female with bilateral breast cancer and no reported family history of cancer. Therefore, this variant was classified as a Pathogenic (Table 1).

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