Submissions for variant NM_007294.4(BRCA1):c.2475del (p.Asp825fs)

gnomAD frequency: 0.00001  dbSNP: rs80357970

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031053	SCV000282281	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	RCV000047850	SCV000075863	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp825Glufs*21) 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 (rs80357970, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 8595428, 18465347, 20104584, 22160602, 22516946, 23199084, 23704984, 24307375, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as 2594delC. ClinVar contains an entry for this variant (Variation ID: 37472). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131352	SCV000186327	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	clinical testing	The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing a translational frameshift with a predicted alternate stop codon (p.D825Efs*21). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date and has been described as a Scandinavian/Northern European founder mutation (Plummer SJ et al. Hum. Mol. Genet. 1995 Oct;4:1989-91; Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Lancaster JM et al. Br. J. Cancer. 1998 Dec;78:1417-20; Johannsson O et al. Eur. J. Cancer. 1999 Aug;35:1248-57; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Thomassen M et al. Acta Oncol. 2008;47:772-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Janaviius R. EPMA J. 2010 Sep;1:397-412; Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Schneegans SM et al. Fam. Cancer, 2012 Jun;11:181-8; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Maxwell KN et al. Nat Commun, 2017 08;8:319; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in familial prostate cancer cohorts (Leongamornlert D et al. Br. J. Cancer. 2012 May;106:1697-701; Li D et al. Front Biosci (Landmark Ed). 2013 Jun;18:1445-59), as well as a uterine serous carcinoma cohort (Pennington KP et al. Cancer, 2013 Jan;119:332-8). It was also seen in a male patient with pancreatic cancer (Ibrahim M et al. BMC Cancer. 2018 02;18(1):179). Of note, this alteration is also designated as 2594delC and rs80357970 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031053	SCV000195906	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000236906	SCV000292513	pathogenic	not provided	2022-06-17	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 a personal or family history consistent with pathogenic variants in this gene, and considered a common founder variant in the Scandinavian population (Plummer 1995, Janaviius 2010, Leongamornlert 2012, Schneegans 2012, Pennington 2013, Cunningham 2014, Maxwell 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2594delC; This variant is associated with the following publications: (PMID: 22811390, 22516946, 17694537, 8595428, 23747895, 26833046, 28476184, 29625052, 26689913, 24504028, 22160602, 23199084, 24728189, 23704984, 17688236, 25452441, 18465347, 20104584, 28049106, 28087643, 27798111, 27375368, 28776284, 28831036, 29339979, 29433453, 30720243, 30322717, 32050665, 31263571, 31883735, 11391658, 34399810, 32719484, 33087929)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236906	SCV000296289	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 31263571 (2019), 24504028 (2014), 22811390 (2013), 20104584 (2010), 18465347 (2008), 8595428 (1995)), pancreatic cancer (PMID: 29433453 (2018)), renal cancer (PMID: 32782288 (2020)), and prostate cancer (PMID: 22516946 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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	RCV000031053	SCV000325365	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031053	SCV000564368	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-21	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000047850	SCV000586884	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000031053	SCV000677643	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131352	SCV000683038	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-31	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. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047850	SCV000698959	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-08	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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. c.2515delC, c.2679_2682delGAAA, c.2681_2682delAA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121366 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature, and has been described as a common mutation in individuals of Scandinavian ancestry. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000474	SCV001157346	pathogenic	not specified	2019-03-25	criteria provided, single submitter	clinical testing	The BRCA1 c.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome (Cunningham 2014, Pennington 2013, Schneegans 2012). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 37472). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Pennington K et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013; 119(2):332-8. Schneegans S et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012; 11(2):181-8.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031053	SCV001428903	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-23	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000031053	SCV001434305	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-07	criteria provided, single submitter	clinical testing	This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result in an unstable transcript that is degraded by nonsense-mediated decay, a well-established mechanism of disease for the BRCA1 gene (Borg 2010). In the literature, this variant has been observed in individuals with breast cancer, ovarian cancer, and prostate cancer and has been noted to occur more commonly in individuals of Scandinavian descent (Cunningham (2014), Janavicius (2010), Larsen (2013), Leongamornlert (2012), Schneegans (2012), Thomassen (2008)). Based on this information, we consider this variant to be pathogenic. PS4; PVS1
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031053	SCV001434971	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-04-30	criteria provided, single submitter	clinical testing	This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 8595428, 18465347). Therefore, the c.2475delC (p.Asp825Glufs*21) variant in the BRCA1 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236906	SCV001447426	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000236906	SCV001449778	pathogenic	not provided	2014-09-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236906	SCV002551018	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482928	SCV002790692	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-02-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236906	SCV003811755	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031053	SCV004215067	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964822	SCV004782881	pathogenic	BRCA1-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian cancer (Maxwell et al. 2017. PubMed ID: 28831036; Cunningham et al. 2014. PubMed ID: 24504028), pancreatic cancer (Ibrahim et al. 2018. PubMed ID: 29433453), and prostate cancer (Leongamornlert et al. 2012. PubMed ID: 22516946). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37472/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031053	SCV000053647	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-02-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031053	SCV000144450	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	RCV000047850	SCV000587221	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	RCV000785403	SCV000923975	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV000047850	SCV001749976	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 12/24/2018 by Invitae and 11/29/2016 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
BRCAlab, Lund University	RCV000031053	SCV002589097	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing