rs80357919
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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.843_846del(p.Ser282TyrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,474 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: 6.8e-7 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.22
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 17-43094684-ATGAG-A is Pathogenic according to our data. Variant chr17-43094684-ATGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 17683.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094684-ATGAG-A is described in Lovd as [Pathogenic]. Variant chr17-43094684-ATGAG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.843_846del | p.Ser282TyrfsTer15 | 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.843_846del | p.Ser282TyrfsTer15 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461474Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726994
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:36
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:15
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1999 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 28, 2013 | - - |
| 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 | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 03, 2023 | Criteria applied: PVS1,PS4,PM2_SUP - |
| 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 | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS4_STR, PM2_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 28, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM2_supporting; PM5_PTC_Strong - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jun 28, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 25, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 282 and the creation of a premature translation stop signal 15 amino acid residues later- p.(Ser282Tyrfs). This is expected to result in an absent or disrupted protein product.Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747).This mutation has been described in the mutation database ClinVar (Variation ID: 17683). - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2021 | 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; Reported in numerous individuals with personal and/or family histories of breast and/or ovarian cancer (Wagner 1998, Janezic 1999, Stegel 2011, Zhang 2011, Pern 2012, Song 2014, Muendlein 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 962del4 and 962_965delCTCA; This variant is associated with the following publications: (PMID: 10196379, 9663595, 21324516, 23110154, 22366370, 21232165, 23397983, 23635950, 24797986, 24728189, 27221827, 25971625, 27533253, 26306726, 25066507, 18489799, 11179017, 27062684, 29339979, 28324225, 31159747, 32341426, 26681312) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Ser282TyrfsX15 variant has been reported in 25 of 3463 probands with breast or ovarian cancer (Anton-Culver_2000_10882857, Capalbo_2006_16760289, Wagner_1998_9663595, Zhang_2011_21324516, Machackova_2008_18489799, Janezic_1999_10196379, http://research.nhgri.nih.gov/bic/). In addition, The p.Ser282TyrfsX15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 282 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the BRCA1 gene, which makes it highly likely that the p.Ser282TyrfsX15 variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital | Aug 23, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 09, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17683). This variant is also known as 962del4. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9663595, 10196379, 17319787, 21203900, 21324156, 23110154). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser282Tyrfs*15) 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 19, 2020 | The p.Ser282TyrfsX15 variant in BRCA1 has been reported in 23 individuals with BRCA1-related cancers (first published by Wagner 1998 PMID: 9663595). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17683). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 282 and leads to a premature termination codon 15 amino acids downstream. This alteration is then 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/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. - |
| 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 | Apr 30, 2021 | Variant summary: BRCA1 c.843_846delCTCA (p.Ser282TyrfsX15) 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 254112 control chromosomes (gnomAD and publication data). c.843_846delCTCA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Wagner_1998, Janezic_1999, Judkins_2005, Song_2014, Rebbeck_2018). 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 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Aug 01, 2000 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2022 | The c.843_846delCTCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of four nucleotides at positions 843 to 846, causing a translational frameshift with a predicted alternate stop codon (p.S282Yfs*15). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Janezic SA et al. Hum. Mol. Genet. 1999;8:889-97; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Wagner TM et al. Int. J. Cancer. 1998 July;77:354-60; Tihomirova L et al. Adv Med Sci. 2014 Mar;59:114-9; Pern F et al. PLoS ONE. 2012 Oct;7:e47993; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Dobricic J et al. J. Hum. Genet. 2013 Aug;58:501-7; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this mutation is also designated as 962del4 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 4 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 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. - |
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 | Jul 27, 2021 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 13, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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