rs80357524
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2433del(p.Lys812ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,370 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: 0.0000027 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.115
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 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 17-43093097-TG-T is Pathogenic according to our data. Variant chr17-43093097-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37469.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093097-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43093097-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2433del | p.Lys812ArgfsTer3 | 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.2433del | p.Lys812ArgfsTer3 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250608Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135462
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461370Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2AN XY: 726996
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Jun 11, 2020 | This variant causes a frameshift that leads to a premature termination codon. This variant is predicted to cause loss of normal protein either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported in a number of women with breast and/or ovarian cancer (Ahn et al. 2007; Torres-Mejia et al. 2015; and Weitzel et al. 2013). Based on this evidence we interpret this variant as pathogenic. PS4; PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 29, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jun 29, 2018 | This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer (PMID: 25863477, 16455195, 25371446, 23233716). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/245,372) and thus is presumed to be rare. Based on the available evidence, the c.2433delC (p.Lys812ArgfsTer3) variant is classified as pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | - | - - |
| 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 | Baylor Genetics | Mar 19, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2018 | Variant summary: BRCA1 c.2433delC (p.Lys812ArgfsX3) 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 8.1e-06 in 245706 control chromosomes (gnomAD). The variant, c.2433delC, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Han_2006, Weitzel_2005, Lim_2009, Vogel_2007, John_2007, Mgbemena_2017). 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 ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 27, 2022 | - - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Lys812Argfs*3) 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 (rs80357524, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16030099, 22798144, 23233716). This variant is also known as 2552delC. ClinVar contains an entry for this variant (Variation ID: 37469). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2023 | The BRCA1 c.2433del; p.Lys812ArgfsTer3 variant (rs80357524), also reported as 2552delC, has been described in multiple individuals affected with breast and/or ovarian cancer and is a recurrent variant in Hispanic and Korean populations (Ahn 2007, Kim 2012, Tung 2015, Vogel 2007, Weitzel 2005). It is reported as a pathogenic variant by multiple sources in ClinVar (Variation ID: 37469) and is described on only 2 alleles 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 pathogenic. REFERENCES Ahn S et al. BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations. Cancer Lett. 2007 Jan 8;245(1-2):90-5. Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012 Aug;134(3):1315-26. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Vogel K et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol. 2007 Oct 10;25(29):4635-41. Weitzel J et al. Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1666-71. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 10, 2023 | 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: 30350268 (2018), 29240602 (2018), 23233716 (2013), 22217648 (2012), 20104584 (2010)). The frequency of this variant in the general population, 0.000008 (2/250608 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2023 | 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; 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 2552delC; This variant is associated with the following publications: (PMID: 22798144, 25628955, 20104584, 29673794, 34490083, 29922827, 28888541, 23233716, 19241424, 17591843, 17100994, 16949048, 16455195, 16030099, 19499246, 25863477, 16685647, 22217648, 19967274, 25371446, 26402875, 28985766, 26295337, 30350268, 30309222, 17925560, 16267036, 30274973, 30720243, 32868804, 28111427, 34645131) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 27, 2022 | 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 over 10 individuals affected with breast and ovarian cancer (PMID: 16030099, 16685647, 16949048, 16455195, 17925560, 18159056, 19499246, 20104584, 22798144, 25186627, 25371446, 26402875, 33471991, 34063308) and has been observed to be a recurrent mutation in Latino and Korean populations (PMID: 17925560, 22798144, 26402875). This variant has been identified in 2/250608 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2021 | The c.2433delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2433, causing a translational frameshift with a predicted alternate stop codon (p.K812Rfs*3). This mutation has been reported in numerous HBOC patients and families (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Kim BY et al. Biochem Biophys Res Commun, 2006 Oct;349:604-10; Han SH et al. Clin Genet, 2006 Dec;70:496-501; Ahn SH et al. Cancer Lett, 2007 Jan;245:90-5; Vogel KJ et al. J Clin Oncol, 2007 Oct;25:4635-41; John EM et al. JAMA, 2007 Dec;298:2869-76; Hall MJ et al. Cancer, 2009 May;115:2222-33; Lim MC et al. J Cancer Res Clin Oncol, 2009 Nov;135:1593-9; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Jang JH et al. J. Hum. Genet., 2012 Mar;57:212-5; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Weitzel JN et al. J Clin Oncol, 2013 Jan;31:210-6; Tung N et al. Cancer, 2015 Jan;121:25-33; Torres-Mejía G et al, 2015 Mar;24:498-505; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68; Choi MC et al. Int J Gynecol Cancer, 2015 Oct;25:1386-91; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with pancreatic cancer and acute myeloid leukemia (Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Kim B et al. Sci Rep, 2020 08;10:14297). Of note, this alteration is also designated as 2552delC 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. - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 08, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Lys812ArgfsX3 deletion variant was identified in at least 13 of 117374 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer, and was not identified in 334 control chromosomes from healthy individuals (Borg 2010, Han 2006, Judkins 2005, Weber 2006, Weitzel 2005). The variant was also identified in dbSNP (ID: rs80357524 ) “With pathogenic allele, HGMD, LOVD, COSMIC, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project (derived from Myriad reports); classified as pathogenic by Ambry Genetics), the BIC database (11X with clinical importance, classified as pathogenic), and UMD (1X as a causal variant). The p.Lys812ArgfsX3deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 812 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 23, 2024 | The BRCA1 c.2433delC variant is predicted to result in a frameshift and premature protein termination (p.Pro811Profs*4). This variant has been reported to be causative for Hereditary Breast and Ovarian Cancer syndrome (HBOC) (Kim et al. 2012. PubMed ID: 22798144; Weitzel et al. 2005. PubMed ID: 16030099). This variant (also known as c.2552delC) has been reported in at least 10 individuals (including 8 individuals from the Breast Cancer Information Core database) all of Hispanic origin with a family history of breast and ovarian cancers (Weitzel et al. 2005 PubMed ID: 16030099). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37469/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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