Submissions for variant NM_007294.4(BRCA1):c.5177_5180del (p.Arg1726fs)

dbSNP: rs80357867

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031225	SCV000300220	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167855	SCV000076856	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	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. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357975, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150171, 22923021, 23397983, 24504028, 26287763, 27831900). This variant is also known as 5296del4. ClinVar contains an entry for this variant (Variation ID: 37644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131829	SCV000186884	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	clinical testing	The c.5177_5180delGAAA pathogenic mutation, located in coding exon 17 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 5177 to 5180, causing a translational frameshift with a predicted alternate stop codon (p.R1726Kfs*3). This mutation has been reported in multiple individuals and families of various ethnicities with clinical histories suggestive of hereditary breast and ovarian cancer including early-onset breast cancer (earliest published age of onset is 24), bilateral breast cancer, triple-negative breast cancer, ovarian cancer, and male breast cancer (Gao Q et al. Am. J. Hum. Genet. 1997 May;60:1233-6; Tai YC et al. J. Natl. Cancer Inst. 2007 Dec;99:1811-4; Robertson L et al. Br. J. Cancer 2012 Mar;106:1234-8; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Ewald IP et al. Genet. Mol. Biol. 2016 Apr-Jun;39:223-31; Natarajan P et al. Sci. Transl. Med. 2016 Nov;8:364ra151; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Sandoval RL et al. PLoS One. 2021 Feb;16:e0247363). Of note, this alteration is also designated as 5296del4 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	RCV000048843	SCV000210055	pathogenic	not provided	2020-08-18	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 several individuals and families with breast and/or ovarian cancer (Gao 1997, Tai 2007, Song 2014, Pal 2015, Ewald 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 5296_5299delGAAA; This variant is associated with the following publications: (PMID: 25452441, 24504028, 9150171, 21232165, 24728189, 16234499, 25330149, 9667259, 26287763, 27469594, 25556971, 26843898, 22923021, 25085752, 23397983, 27303907, 28008555, 28127413, 28785956, 27831900, 28324225, 18042939, 27425403, 29907814, 29161300, 30322717, 26848151, 31447099)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048843	SCV000296306	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	The BRCA1 c.5177_5180del (p.Arg1726Lysfs*3) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals/families with breast and/or ovarian cancer (PMID: 34717758 (2021), 33646313 (2021), 32772980 (2020), 26287763 (2015), 25452441 (2015), 24504028 (2014), 23397983 (2014), 22923021 (2012)), including male breast cancer (PMID: 28008555 (2017)), as well as an individual unaffected by cancer (PMID: 27831900 (2016)). The frequency of this variant in the general population, 0.000008 (2/251090 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000031225	SCV000326194	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167855	SCV000605751	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Arg1726LysfsX3 variant in BRCA1 has been reported in >30 individuals with BRCA1-associated cancers (Gao 1997 PMID:9150171, Cunningham 2014 PMID:24504028, Stegel 2011 PMID:21232165, Trujillano 2015 PMID:25556971, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). It has also been identified in 0.002% (1/41446) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1726 and leads to a premature termination codon 3 amino acids downstream. This alteration 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 hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37644). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1.
GeneKor MSA	RCV000048843	SCV000693544	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This is a deletion of 4 base pairs from exon 18 of the BRCA1 mRNA (c.5177_5180delGAAA), causing a frameshift at codon 1726. This deletion creates a premature translation stop signal 3 amino acid residues later and is expected to result in an absent or disrupted protein product. This variant is also known as 5296del4 in the literature and has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 9150171, 22923021, 24504028). The mutation database ClinVar contains entries for this variant (Variation ID: 37644).
Counsyl	RCV000031225	SCV000785673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-10-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048843	SCV000883465	pathogenic	not provided	2017-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167855	SCV000918736	pathogenic	Hereditary breast 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.
Color Diagnostics, LLC DBA Color Health	RCV000131829	SCV001354793	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 18 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 is also known as 5296del4 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in multiple individuals affected with breast and/or ovarian cancer, as well as individuals from hereditary breast and ovarian cancer families (PMID: 18042939, 22923021, 23397983, 24504028, 26287763, 27425403, 27469594, 28008555, 28324225, 29907814, 33606809, 34717758). In a large breast cancer case-control study, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991). This variant has also been identified in 2/251090 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031225	SCV001440670	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-12	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000048843	SCV001447715	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031225	SCV001499707	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000048843	SCV001501173	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000048843	SCV002020112	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167855	SCV002025909	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
DASA	RCV000031225	SCV002107160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-05	criteria provided, single submitter	clinical testing	The c.5177_5180del ;p.(Arg1726Lysfs*3) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37644; PMID: 9150171; PMID: 22923021; PMID: 23397983; PMID: 24504028; PMID: 26287763; PMID: 27831900)PS4. The variant is present at low allele frequencies population databases (rs80357867 – gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics	RCV000031225	SCV004212700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031225	SCV004817578	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-10	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 18 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 is also known as 5296del4 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in multiple individuals affected with breast and/or ovarian cancer, as well as individuals from hereditary breast and ovarian cancer families (PMID: 18042939, 22923021, 23397983, 24504028, 26287763, 27425403, 27469594, 28008555, 28324225, 29907814, 33606809, 34717758). In a large breast cancer case-control study, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991). This variant has also been identified in 2/251090 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000167855	SCV005045703	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-05	criteria provided, single submitter	clinical testing	The c.5177_5180del (p.Arg1726Lysfs*3) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 9150171, 18042939, 21232165, 22333603, 22923021, 23397983, 24504028, 24728189, 25556971, 26287763, 27303907, 27831900, 28008555, 28324225). This variant has been identified in 2/251090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.5177_5180del (p.Arg1726Lysfs*3) variant of the BRCA1 gene is classified as pathogenic.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000031225	SCV005201112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-09-05	criteria provided, single submitter	clinical testing	Null variant (frame-shift) in gene BRCA1, predicted to cause NMD. Loss-of-function is a known mechanism of disease (gene has 3 663 reported pathogenic LOF variants). The exon affects 1 functional domain: UniProt protein BRCA1_HUMAN domain 'BRCT 1'. The exon contains 46 pathogenic variants. The truncated region contains 450 pathogenic variants (PVS1). Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars (reviewed Jul '24, 28 submissions of which 4 are from high confidence submitters) (PP5). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA1, good gnomAD genomes coverage = 31.0.GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA1, good gnomAD exomes coverage = 31.5 (PM2). We observed this variant in a 61-year-old female patient with Breast-ovarian cancer, familial, 1.
Mayo Clinic Laboratories, Mayo Clinic	RCV000048843	SCV005413223	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	PM5_strong, PVS1
Sharing Clinical Reports Project (SCRP)	RCV000031225	SCV000053825	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-05-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031225	SCV000145373	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167855	SCV000587473	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785209	SCV000923777	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257554	SCV001434380	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
BRCAlab, Lund University	RCV000031225	SCV004243936	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing