rs80357887
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.470_471del(p.Ser157Ter) 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.23
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]
Genome browser will be placed here
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 17-43099850-TAG-T is Pathogenic according to our data. Variant chr17-43099850-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37608.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099850-TAG-T is described in Lovd as [Pathogenic]. Variant chr17-43099850-TAG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.470_471del | p.Ser157Ter | frameshift_variant | 7/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.470_471del | p.Ser157Ter | frameshift_variant | 7/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.470_471del;p.(Ser157*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37608; PMID: 11149413; PMID: 22970155; PMID: 23683081; PMID: 29907814) - PS4. This variant is not present in population databases (rs80357887- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 17, 2022 | - - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| 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, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 29, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP1 moderated - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 27, 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 | - - |
| not provided, no classification provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2020 | Variant summary: BRCA1 c.470_471delCT (p.Ser157X) 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 251450 control chromosomes. c.470_471delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (delaHoya_2002, Judkins_2005, Kwong_2012, Peixoto_2014). These data indicate that the variant is very likely to be associated with disease. 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. - |
| Pathogenic, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| 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 15, 2024 | This sequence change creates a premature translational stop signal (p.Ser157*) 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: 11149413, 22970155, 23683081, 24916970). This variant is also known as 589delCT. ClinVar contains an entry for this variant (Variation ID: 37608). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 19, 2022 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with suspected hereditary breast/ovarian cancer syndrome in the published literature (PMIDs: 30702160 (2019), 29907814 (2018), 29752822 (2018), 29446198 (2018), 29176636 (2018), 24916970 (2015), 23683081 (2013), 22970155 (2012), 22762150 (2012), 18627636 (2008), 11149413 (2001), and 10340909 (1999)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 15, 2022 | The BRCA1 c.470_471delCT; p.Ser157Ter variant (rs80357887), also known as 589delCT, is reported in several individuals and families with hereditary breast and/or ovarian cancer (de la Hoya 2001, de lay Hoya 2002, Fernandes 2016, Wen 2018). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37608) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes two nucleotides, leading to an immediate nonsense codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: de la Hoya M et al. Spanish family study on hereditary breast and/or ovarian cancer: analysis of the BRCA1 gene. Int J Cancer. 2001 Jan 1;91(1):137-40. PMID: 11149413. de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. PMID: 11802208. Fernandes GC et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016 Dec 6;7(49):80465-80481. PMID: 27741520. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. PMID: 28993434. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | 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 (Tang 1999, de la Hoya 2001, Kwong 2012, Blay 2013, Peixoto 2015); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 589_590delCT; This variant is associated with the following publications: (PMID: 17603881, 24249303, 11149413, 22970155, 26187060, 24916970, 28127413, 24578176, 27157322, 12955716, 23199084, 23683081, 18627636, 10340909, 27553291, 28961279, 11802208, 29752822, 28993434, 30702160, 27741520, 29176636, 31825140, 30787465, 32101877) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 19, 2021 | This variant deletes 2 nucleotides in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 589delCT and 589_590delCT in the literature. 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 over 10 individuals affected with breast and ovarian cancer (PMID: 11802208, 12955716, 16998791, 20617377, 22970155, 27553368, 27741520, 29752822) and in suspected hereditary breast and ovarian cancer families (PMID: 23683081, 24249303, 24916970). 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 | Apr 25, 2022 | The c.470_471delCT pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 470 to 471, causing a translational frameshift with a predicted alternate stop codon (p.S157*). This alteration has been identified as a recurrent mutation in both Spanish and Southern Chinese breast and/or ovarian cancer cohorts (de la Hoya M et al. Int. J. Cancer 2001 Jan;91:137-40; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Kwong A et al. PLoS ONE 2012 Sep;7:e43994). This mutation has also been reported in multiple international HBOC cohorts (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Fernandes GC et al. Oncotarget 2016 Oct;7(49):80465-80481; Bhaskaran SP et al. Int. J. Cancer 2019 Jan; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Li JY et al. Int. J. Cancer 2019 01;144:281-289; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 589_590delCT 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 | May 13, 2022 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 01, 2024 | The BRCA1 c.470_471delCT variant is predicted to result in premature protein termination (p.Ser157*). This variant, also referred to in the literature as c.589delCT, has been reported in several individuals and families with hereditary breast and/or ovarian cancer (de la Hoya et al. 2001. PubMed ID: 11149413; de la Hoya et al. 2002. PubMed ID: 11802208; Kwong et al. 2012. PubMed ID: 22970155; Peixoto et al. 2014. PubMed ID: 24916970). This variant has not been reported in a large population database, indicating this variant is rare, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37608/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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