Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3029_3030delCT(p.Pro1010ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P1010P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43092500-CAG-C is Pathogenic according to our data. Variant chr17-43092500-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 54757.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:7
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein. -
Oct 18, 2016
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Jan 02, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Jan 06, 2024
All of Us Research Program, National Institutes of Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant deletes 2 nucleotides 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 detected in at least 4 individuals affected with breast cancer and over 10 hereditary breast and ovarian cancer families (PMID: 18159056, 19241424, 20104584, 21080930, 25628955, 28127413). 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. -
The c.3029_3030delCT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3029 to 3030, causing a translational frameshift with a predicted alternate stop codon (p.P1010Rfs*7). This mutation has been reported in several Hispanic breast/ovarian cancer families (John EM et al. JAMA. 2007 Dec;298(24):2869-76; Hall MJ et al. Cancer. 2009 May;115(10):2222-33; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71). Of note, this alteration is also designated as 3148delCT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Mar 24, 2025
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant deletes 2 nucleotides 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 detected in at least 4 individuals affected with breast cancer and over 10 hereditary breast and ovarian cancer families (PMID: 18159056, 19241424, 20104584, 21080930, 25628955, 28127413). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 6.228 from log(LR)=0.794 for 4 carriers (PMID: 31853058). 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. -
Dec 16, 2021
Sema4, Sema4
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation
- -
Hereditary breast ovarian cancer syndromePathogenic:3
Sep 22, 2023
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.3029_3030del (p.Pro1010Argfs*7) variant of the BRCA1 gene creates an early stop codon. It is predicted to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 16267036, 18159056, 19241424, 20104584, 21080930, 25186627, 25628955, 28127413, 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore this variant is classified as pathogenic. -
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Pro1010Argfs*7) 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 cancer (PMID: 18159056, 20104584). This variant is also known as 3148delCT. ClinVar contains an entry for this variant (Variation ID: 54757). For these reasons, this variant has been classified as Pathogenic. -
Sep 28, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.3029_3030delCT (p.Pro1010ArgfsX7) 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 was absent in 251110 control chromosomes. c.3029_3030delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Borg_2010, John_2007, Hall_2009, Rebbeck_2018). Eight 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. -
not providedPathogenic:2
Jan 25, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method: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 cancer (PMIDs: 25628955 (2015), 25186627 (2015), 18159056 (2007), 20104584 (2010)). 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. -
Jul 15, 2019
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method: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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26295337, 19241424, 21532809, 20104584, 26564481, 25371446, 25628955, 21080930, 18159056, 28127413, 28152038) -