Submissions for variant NM_007294.4(BRCA1):c.2457del (p.Asp821fs)

dbSNP: rs80357669

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031052	SCV000299772	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	RCV000167767	SCV000075858	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp821Ilefs*25) 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 (rs80357669, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8807330, 23269703, 24504028, 24728189, 26681312, 26718727). This variant is also known as 2576delC, S819fs, and 819delC. ClinVar contains an entry for this variant (Variation ID: 37471). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131356	SCV000186332	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The c.2457delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2457, causing a translational frameshift with a predicted alternate stop codon (p.D821Ifs*25). This mutation has been observed in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Pal T et al. Cancer 2005 Dec;104:2807-16; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Bernards SS et al. Gynecol. Oncol. 2016 Feb;140:221-5; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition, in the first validated report of biallelic BRCA1 mutations, this alteration was detected in trans with a second BRCA1 mutation (p.V1736A) in a woman diagnosed with ovarian cancer at age 28 whose complex medical history also included short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy (Domchek S et al. Cancer Discov. 2013 Apr;3:399-405). Of note, this alteration is also designated as 2576delC 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	RCV000031052	SCV000195904	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000047845	SCV000209881	pathogenic	not provided	2019-06-05	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; Identified in individuals with BRCA1-related cancers (Couch 1996, Schorge 2001, Pal 2005, Cunningham 2014, Couch 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 2576delC; This variant is associated with the following publications: (PMID: 18824701, 16267036, 23725378, 23199084, 8606385, 26845104, 24728189, 26884819, 31871297, 29133208, 23269703, 29625052, 24504028, 22010008, 11606101, 20665887, 16284991, 27836010, 26718727, 25452441, 8807330, 29435075, 29478780, 29712865, 30720243, 30322717, 30309722, 26689913)
Eurofins Ntd Llc (ga)	RCV000047845	SCV000224993	pathogenic	not provided	2014-09-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000031052	SCV000266028	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047845	SCV000296345	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	The BRCA1 c.2457del (p.Asp821Ilefs*25) 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 affected with breast and/or ovarian cancer (PMIDs: 26718727 (2016), 27836010 (2016), 27083775 (2016), 26845104 (2016), 23269703 (2013)). 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	RCV000031052	SCV000325361	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	RCV000167767	SCV000605753	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-28	criteria provided, single submitter	clinical testing	The p.Asp821fs variant in BRCA1 has been reported in >50 individuals with BRCA1- associated cancers (Couch 1996, Bernards 2016, Cunningham 2014, Domchek 2013, Br east Cancer Information Core (BIC), Sharing Clinical Reports Project). This vari ant has been identified in 2/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80357669). This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 821 and leads to a premature termination codon 25 am ino acids downstream. This alteration is then predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the BRCA1 gene is an establis hed disease mechanism in individuals with hereditary breast and ovarian cancer ( HBOC). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299772.2). In summary, t his variant meets criteria to be classified as pathogenic for HBOC in an autosom al dominant manner.
Counsyl	RCV000031052	SCV000677642	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131356	SCV000683036	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-20	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 reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 8807330, 11773283, 14760071, 16284991, 17688236, 18284688, 19340607, 22010008, 23269703, 23725378, 24504028, 24728189, 26681312, 26718727, 26845104, 3347199; Leiden Open Variation Database DB-ID BRCA1_003958) and colorectal cancer (PMID: 29478780). This variant has been identified in 3/250740 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	RCV000167767	SCV000698956	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2457delC (p.Asp821Ilefs) 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.2940delA). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in numerous HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000047845	SCV001716308	pathogenic	not provided	2019-09-26	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4, PP5
Revvity Omics, Revvity	RCV000047845	SCV002023530	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131356	SCV002538125	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002482927	SCV002779819	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031052	SCV004212677	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031052	SCV004818180	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-28	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 reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 8807330, 11773283, 14760071, 16284991, 17688236, 18284688, 19340607, 22010008, 23269703, 23725378, 24504028, 24728189, 26681312, 26718727, 26845104) and colorectal cancer (PMID: 29478780). This variant has been identified in 3/250740 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.
Sharing Clinical Reports Project (SCRP)	RCV000031052	SCV000053646	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031052	SCV000144441	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000031052	SCV000207338	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-06	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167767	SCV000587219	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
OMIM	RCV000585855	SCV000693736	pathogenic	Fanconi anemia, complementation group S	2013-04-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758606	SCV005361469	pathogenic	BRCA1-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The BRCA1 c.2457delC variant is predicted to result in a frameshift and premature protein termination (p.Asp821Ilefs*25). This variant has been reported to be causative for breast and ovarian cancer (Plummer et al. 1995.PubMed ID: 8595428; Domchek et al. 2013. PubMed ID: 23269703; Cunningham et al. 2014. PubMed ID: 24504028; AlDubayan et al. 2018. PubMed ID: 29478780; Carter et al. 2018. PubMed ID: 30322717; Soussi et al. 2019. PubMed ID: 30720243). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37471/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.