rs80357635
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.3228_3229del(p.Gly1077AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 frameshift
ENST00000357654.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.81
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-43092301-CCT-C is Pathogenic according to our data. Variant chr17-43092301-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37516.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092301-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43092301-CCT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3228_3229del | p.Gly1077AlafsTer8 | frameshift_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3228_3229del | p.Gly1077AlafsTer8 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250376Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135310
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461648Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727128
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 30, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Nov 17, 2016 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 18, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 30, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2023 | Founder pathogenic variant in the Norwegian population (Ferla 2007); 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 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 3347_3348del, 3345delAG, and 3347delAG; This variant is associated with the following publications: (PMID: 10359546, 24549055, 20104584, 26350514, 27356891, 27425403, 27836010, 29061375, 29339979, 29907814, 34413315, 32438681, 31336956, 29922827, 28888541, 19656164, 17591843, 10660329, 18821011, 14522380, 17574839, 15477862, 18819001, 22798144, 17063270, 10595257, 24312913, 15735322, 26852130, 23776375, 24131976, 19383375, 9544766, 12543786, 15519522, 18158280, 16764716, 28161869, 28637432, 28127413, 28664506, 29470806, 28724667, 29161300, 30702160, 28111427, 30720243, 32854451, 31825140, 33646313, 32719484, 11720839, 35710434, 35864222, 34981296) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 26, 2021 | This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 34072659 (2021), 32854451 (2020), 18821011 (2009), and 11720839 (2001)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Gly1077Alafs*8) 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 (rs80357635, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11720839, 14522380, 15477862, 16030099, 17574839, 17591843, 18819001, 18821011, 19837273, 19941167, 20104584, 22798144, 24549055, 26350514). It is commonly reported in individuals of Norwegian ancestry (PMID: 11720839, 14522380, 15477862, 16030099, 17574839, 17591843, 18819001, 18821011, 19837273, 19941167, 20104584, 22798144, 24549055, 26350514). This variant is also known as 3347delAG and c.3228delAG. ClinVar contains an entry for this variant (Variation ID: 37516). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2023 | Variant summary: BRCA1 c.3228_3229delAG (p.Gly1077AlafsX8) 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. The variant allele was found at a frequency of 4e-06 in 250376 control chromosomes. c.3228_3229delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Papi_2009, Moller_2007). 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. The following publications have been ascertained in the context of this evaluation (PMID: 18821011, 17574839). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 30, 2019 | The c.3228_3229del (p.Gly1077Alafs*8) variant in the BRCA1 gene is located on exon 10 and introduces 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: 11720839, 14522380, 14531499, 15477862, 16030099, 17574839, 17591843, 18819001, 18821011, 19837273, 19941167, 20104584, 22798144, 24549055, 26350514, 27425403, 28637432, 28724667, 29371908, 32438681, 33403015, 33471991, 34072659). This variant is a founder mutation in Norwegian and Italian populations (PMID: 17591843, 18821011). The variant is reported in ClinVar as pathogenic (ID: 37516) and reviewed by the expert panel. This variant is rare (1/250376 chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2021 | The c.3228_3229delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3228 to 3229, causing a translational frameshift with a predicted alternate stop codon (p.G1077Afs*8). This mutation has been reported in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Aretini P et al. Breast Cancer Res Treat, 2003 Sep;81:71-9; Bjørge T et al. Br. J. Cancer, 2004 Nov;91:1829-34; Ottini L et al. Breast Cancer Res Treat, 2009 Aug;116:577-86; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13; Lin PH et al. Oncotarget, 2016 Feb;7:8310-20; Alemar B et al. Cancer Genet, 2016 09;209:417-422; Høberg-Vetti H et al. Eur J Hum Genet, 2016 06;24:881-8; Grindedal EM et al. BMC Cancer, 2017 Jun;17:438; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Fanale D et al. Cancers (Basel), 2020 Aug;12; Santonocito C et al. Cancers (Basel), 2020 May;12; Incorvaia L et al. Ther Adv Med Oncol, 2020 Dec;12). Due to its prevalence in Norway and Tuscany, this alteration has also been recognized as a founder mutation in these two populations (Møller P et al. Eur. J. Cancer. 2001 Dec;37:2428-34; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504). Of note, this alteration is also designated as c.3226_3227delAG, 3347delAG and 3345delAG in the 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 06, 2023 | 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. This variant has been reported in over 30 individuals and families affected with breast and/or ovarian cancer (PMID: 11720839, 14522380, 14531499, 15477862, 17574839, 18819001, 18821011, 19837273, 20104584, 22798144, 24549055, 26350514, 27425403, 28637432, 28724667, 29371908, 33471991; Leiden Open Variation Database DB-ID BRCA1_000674), and it is considered a founder or recurrent mutation in the Norwegian and Italian populations (PMID: 17591843, 18821011). This variant has been identified in 61 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/250376 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. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 17, 2020 | - - |
BRCA1-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 03, 2024 | 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. This variant has been reported in over 30 individuals and families affected with breast and/or ovarian cancer (PMID: 11720839, 14522380, 14531499, 15477862, 17574839, 18819001, 18821011, 19837273, 20104584, 22798144, 24549055, 26350514, 27425403, 28637432, 28724667, 29371908, 33471991; Leiden Open Variation Database DB-ID BRCA1_000674), and it is considered a founder or recurrent mutation in the Norwegian and Italian populations (PMID: 17591843, 18821011). This variant has been identified in 61 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/250376 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. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
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