Submissions for variant NM_007294.4(BRCA1):c.3005del (p.Asn1002fs)

dbSNP: rs80357601

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019238	SCV000299869	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	RCV000048039	SCV000076052	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1002Thrfs*22) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894492, 17688236, 20104584, 24728189, 25452441). This variant is also known as 3121delA or 3124delA. ClinVar contains an entry for this variant (Variation ID: 17669). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000159912	SCV000210031	pathogenic	not provided	2022-12-12	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 a personal or family history consistent with pathogenic variants in this gene (Simard et al., 1994; Gayther et al., 1999; Borg et al., 2010; Song et al., 2014; Couch et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3124del; This variant is associated with the following publications: (PMID: 14648706, 20104584, 34413315, 28888541, 30678073, 24728189, 10486320, 7894492, 25452441, 26295337, 29339979, 32050665)
Ambry Genetics	RCV000163096	SCV000213603	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The c.3005delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3005, causing a translational frameshift with a predicted alternate stop codon (p.N1002Tfs*22). This mutation has been reported in multiple individuals with personal and/or family history of breast and/or ovarian cancer (Simard J et al. Nat. Genet., 1994 Dec;8:392-8; Ramus SJ et al. Hum. Mutat., 2007 Dec;28:1207-15; Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40;Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11). 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.
Counsyl	RCV000019238	SCV000220519	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-16	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159912	SCV000296421	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	The BRCA1 c.3005del (p.Asn1002Thrfs*22) 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: 25452441 (2015), 24728189 (2014), 20104584 (2010)). The frequency of this variant in the general population, 0.000004 (1/250814 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	RCV000019238	SCV000325522	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019238	SCV000564302	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163096	SCV000683077	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	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: 7837387, 10486320, 16912212, 20104584, 24728189, 25452441, 29446198). This variant has not been identified 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	RCV000048039	SCV000918740	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3005delA (p.Asn1002ThrfsX22) 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 3.9e-06 in 255218 control chromosomes. c.3005delA 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. Seven clinical diagnostic laboratories 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000019238	SCV002061628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-10-15	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4_Supporting
Revvity Omics, Revvity	RCV000159912	SCV003812365	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000019238	SCV004212701	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000019238	SCV004815618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-20	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. 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: 7837387, 10486320, 16912212, 20104584, 24728189, 25452441, 29446198). This variant has not been identified 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048039	SCV004848032	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The p.Asn1002fs variant in BRCA1 has been reported in >20 individuals with BRCA1-associated cancers (Simard 1994, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1002 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299869.2). In summary, the p.Asn1002fs variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
OMIM	RCV000019238	SCV000039526	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019238	SCV000053675	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-12-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019238	SCV000144606	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	RCV000048039	SCV000587270	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159912	SCV000591418	pathogenic	not provided		no assertion criteria provided	clinical testing