Submissions for variant NM_007294.4(BRCA1):c.1510del (p.Arg504fs)

dbSNP: rs80357908

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000030999	SCV000299611	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000130024	SCV000184850	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	The c.1510delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1510, causing a translational frameshift with a predicted alternate stop codon (p.R504Vfs*28). This alteration has been identified in multiple breast and/or ovarian cancer families (Solano, AR et al. Springerplus. 2012 Sep 25;1:20; Sokolenko, AP et al. Hered Cancer Clin Pract. 2009 Jan 26;7(1):2; Machackova, E et al. BMC Cancer. 2008 May 20;8:140). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030999	SCV000325089	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130024	SCV000688341	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 18489799, 19338681, 20960228, 23961350, 30040829, 32772980, 34680878, DOI:10.24075/brsmu.2021.006; Color internal data). This variant has been identified in 1/251044 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985369	SCV001133489	pathogenic	not provided	2019-06-02	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Invitae	RCV000496881	SCV002142914	pathogenic	Hereditary breast ovarian cancer syndrome	2021-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg504Valfs*28) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 18489799, 26689913, 30014164). ClinVar contains an entry for this variant (Variation ID: 37418). This variant is present in population databases (rs80357908, ExAC 0.002%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496881	SCV004039351	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1510delC (p.Arg504ValfsX28) 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 4e-06 in 251044 control chromosomes. c.1510delC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Judkins_2005, Machackova_2008, Sokolenko_2009, Solano_2012). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18489799, 23961350, 19338681). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters, including an expert panel, classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000030999	SCV000053591	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-08-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030999	SCV000144118	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496881	SCV000587145	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030999	SCV000591339	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Arg504ValfsX28 variant was identified in 1 of 2020 proband chromosomes (frequency: 0.0005) from individuals or families with breast and/or ovarian cancer (Machackova 2008). The variant was also identified in dbSNP (ID: rs80357908) as “With Pathogenic allele”, ClinVar and Clinvitae (7x classified as pathogenic by University of Cambridge, COGR, Ambry Genetics, BIC, SCRP, Women's College Hospital, ENIGMA; 1x classification not given by Invitae), GeneInsight-COGR (classified as pathogenic), LOVD 3.0 (1x classified as affects function by ENIGMA), UMD-LSDB (classified as causal), BIC Database (2x classified as pathogenic), and ARUP Laboratories (1x classified as definitely pathogenic). The variant was not identified in the following databases: COSMIC, MutDB, Zhejiang Colon Cancer Database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project or the Genome Aggregation Database. The variant was identified in control databases in 1 of 121170 chromosomes at a frequency of 0.000008 in the following populations: European non-Finnish in 1 of 66608 chromosomes at a frequency of 0.000015 (Exome Aggregation Consortium, March 14, 2016). The c.1510delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 504 and leads to a premature stop codon 28 codons downstream. 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.
CZECANCA consortium	RCV001270965	SCV001451769	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing