17-43074482-C-T
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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.4524G>A(p.Trp1508Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: -0.0220
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 17-43074482-C-T is Pathogenic according to our data. Variant chr17-43074482-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55221.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074482-C-T is described in Lovd as [Pathogenic]. Variant chr17-43074482-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4524G>A | p.Trp1508Ter | stop_gained | 14/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4524G>A | p.Trp1508Ter | stop_gained | 14/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727226
GnomAD4 exome
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3
AN:
1461826
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31
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2
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727226
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:28Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10
| 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 | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 04, 2024 | This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a 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 reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 02, 2010 | - - |
| 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 25, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 17, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pathway Genomics | Oct 30, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not provided Pathogenic:6Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 31, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 26, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 21, 2023 | PP5, PM2, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2023 | Nonsense 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 (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce 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 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 07, 2019 | The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Trp1508*) 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, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2020 | Variant summary: BRCA1 c.4524G>A (p.Trp1508X) 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 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). 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. Twelve 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 19, 2023 | This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2022 | The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A 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. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 16, 2019 | The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 03, 2023 | - - |
Inherited breast cancer and ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | NHS Central & South Genomic Laboratory Hub | Jul 01, 2024 | - - |
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 | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;N;N;N;N;N
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at