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

dbSNP: rs80357888

Total submissions: 28

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, susceptibility to, 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 ovarian cancer syndrome	2023-12-01	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. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357888, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 20104584, 23479189, 23536787, 24372583, 26296701). This variant is also known as 1623del5. ClinVar contains an entry for this variant (Variation ID: 37417). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131841	SCV000186896	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The c.1504_1508delTTAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 1504 to 1508, causing a translational frameshift with a predicted alternate stop codon (p.L502Afs*2). This mutation has been detected in multiple breast and/or ovarian cancer families of various ethnicities to date (Peelen T et al. Am. J. Hum. Genet. 1997 May;60(5):1041-9; Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9; Stavropoulou AV et al. PLoS One. 2013 Mar;8(3):e58182; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12(4):767-77; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Riahi A et al. Clin. Genet. 2015 Feb;87(2):155-60; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103)(Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Of note, this alteration is also designated as 1623del5 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000047499	SCV000210014	pathogenic	not provided	2019-12-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with BRCA1-related cancers (Peelen 1997, Ellingson 2015, Laraqui 2015, Riahi 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1623del5 and 1623_1627delTTAAA; This variant is associated with the following publications: (PMID: 9150151, 26187060, 17262179, 27836010, 25814778, 10737987, 11857748, 23479189, 24372583, 26296701, 27211102, 28127413, 27025497, 26577449, 28152038, 27062684, 29907814, 28993434, 31159747, 30322717, 30720243, 30078507, 30720863, 30702160, 29176636)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000210987	SCV000267856	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047499	SCV000296339	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. It has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9150151 (1997), 24312913 (2013), 23479189 (2013), 27836010 (2016), 28993434 (2018), 23536787 (2013), 24372583 (2015), 30078507 (2018), 30322717 (2018), 30702160 (2019), 30720863 (2019), and 31159747 (2019)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030998	SCV000325084	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000030998	SCV000677638	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131841	SCV000682968	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 15 individuals affected with breast and ovarian cancer (PMID: 11376024, 19491284, 20104584, 21204799, 23479189, 23536787, 24010542, 24372583, 24728189, 26296701, 28993434, 30078507, 30130155, 33471991; Leiden Open Variation Database DB-ID BRCA1_001306; Color internal data). This variant has been identified in 3/251068 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
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, susceptibility to, 1	2017-12-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000047499	SCV001249213	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000210987	SCV001251954	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000210987	SCV001361736	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-31	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. Truncations downstream of this position have been classified as pathogenic by our laboratory. 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 multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. Fourteen clinical diagnostic laboratories, one consortium (CIMBA), and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000047499	SCV001449989	pathogenic	not provided	2019-12-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000030998	SCV002761483	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-08-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000047499	SCV003809679	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030998	SCV004216894	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047499	SCV004242841	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030998	SCV000053590	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030998	SCV000144114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357878	SCV001553472	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Leu502AlafsX2 variant was identified in 11 of 12654 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Borg 2010, de Juan Jimenez 2013, Ellingson 2015, Konstantopoulou 2000, Peelen 1997, Riahi 2015, Stavropoulou 2013, Van Der Merwe 2012, Wong-Brown 2015); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the following databases: dbSNP (ID: rs80357888) as "With Pathogenic allele", ClinVar (13x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in tumour of the ovary), LOVD 3.0 (15x), UMD-LSDB (13x causal), BIC Database (29x pathogenic), and ARUP Laboratories (definitely pathogenic). The variant was not identified in the MutDB or the Zhejiang Colon Cancer Databases. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1504_1508delTTAAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 502 and leads to a premature stop codon at position 503. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000047499	SCV001905899	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000047499	SCV001969020	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000030998	SCV002589083	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing