chr17-43092478-T-TTCTCA
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.3048_3052dupTGAGA(p.Asn1018fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. N1018N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.84
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 17-43092478-T-TTCTCA is Pathogenic according to our data. Variant chr17-43092478-T-TTCTCA is described in ClinVar as [Pathogenic]. Clinvar id is 54763.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251144Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135754
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461712Hom.: 0 Cov.: 50 AF XY: 0.00000688 AC XY: 5AN XY: 727156
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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:10
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 13, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This variant inserts 5 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 is also known as 3166ins5, 3171ins5, and 3172ins5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 7837387, 8644702, 11576847, 11781691, 15951958, 18465347, 18559594, 20104584, 20151938, 24504028, 34680387). This variant has been identified recurrently in the Swedish population and has been established as a founder variant (PMID: 8644702, 11576847, 11781691, 15951958, 20151938, 23199084). This variant has been identified in 90 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/251144 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Oct 18, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 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; Observed in multiple families with breast, ovarian, and/or pancreatic cancers and is the most common Swedish founder variant (Shattuck-Eidens 1995, Johannsson 1996, Bergman 2001, Cunningham 2014); 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 3171ins5 or 3166ins5; This variant is associated with the following publications: (PMID: 18465347, 18559594, 24504028, 11781691, 8644702, 7837387, 23199084, 26295337, 24728189, 28152038, 27720647, 11576847, 27836010, 30720243, 29339979, 32719484, 31447099) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 05, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 22, 2014 | - - |
| 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 | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Asn1018Metfs*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 (rs80357856, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11781691, 15951958, 20151938, 24504028). It is commonly reported in individuals of Western Swedish ancestry (PMID: 11781691, 15951958, 20151938). This variant is also known as 3171ins5. ClinVar contains an entry for this variant (Variation ID: 54763). 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 19, 2020 | The p.Asn1018MetfsX8 variant in BRCA1 has been reported in >40 Caucasian individuals with BRCA1-associated cancers and segregated with disease in > 15 affected relatives (initial description by Shattuck-Eidens 1995 PMID: 7837387). It has also been identified in 0.004% (4/113524) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 10/18/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 54763). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1018 and leads to a premature termination codon 8 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 HBOC. This variant has been characterized by haplotype mapping as a founder mutation in western Sweden, accounting for a majority of BRCA1 variants identified in the region (Bergman 2005 PMID: 15951958). Additional variants involving this codon (c.3052_3053ins5; c.3049_3050ins7; c.3049G>T, p.Glu1017Ter) have been identified in individuals with HBOC and are classified as pathogenic by ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PVS1, PM2, PS4, PP1_Strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2024 | Variant summary: BRCA1 c.3048_3052dupTGAGA (p.Asn1018MetfsX8) 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 1.6e-05 in 254200 control chromosomes. c.3048_3052dupTGAGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 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: , 18465347, 24728189, 7837387, 24240112). ClinVar contains an entry for this variant (Variation ID: 54763). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2022 | The c.3048_3052dupTGAGA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TGAGA at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.N1018Mfs*8). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families and has been established as a Swedish founder mutation and the most recurrent BRCA1 or BRCA2 mutation in this population (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Johannsson O et al. Am J Hum Genet, 1996 Mar;58:441-50; Einbeigi Z et al. Eur J Cancer, 2001 Oct;37:1904-9; Bergman A et al. Eur. J. Hum. Genet. 2001 Oct;9:787-93; Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Thomassen M et al. Acta Oncol, 2008;47:772-7; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Janavicius R. EPMA J. 2010 Sep;1:397-412; Cunningham JM et al. Sci Rep 2014;4:4026; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Nielsen HR et al. Fam Cancer, 2016 10;15:507-12; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). Of note, this alteration is also referred to as 3171ins5, 3172ins5 and 3166ins5 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 03, 2023 | This variant inserts 5 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 is also known as 3166ins5, 3171ins5, and 3172ins5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 7837387, 8644702, 11576847, 11781691, 15951958, 18465347, 18559594, 20104584, 20151938, 24504028, 34680387). This variant has been identified recurrently in the Swedish population and has been established as a founder variant (PMID: 8644702, 11576847, 11781691, 15951958, 20151938, 23199084). This variant has been identified in 90 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 4/251144 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. - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Asn1018MetfsX8 variant was identified in the literature in 6 of 1714 proband chromosomes (frequency: 0.003) from individuals or families with Breast and Ovarian cancers (Hakansson 1997, Thomassen 2008, Kainu 1996, Bergman 2001). The variant was identified in dbSNP (ID: rs80357856) “With pathogenic allele”. In the Exome Aggregation Consortium (ExAC) database the variant was identified in 4 of 66706 European (Non-Finnish) alleles (frequency 6 x 10-5.) The variant was also identified in LOVD 2x classified as pathogenic; the ClinVar database (classified as a pathogenic variant by Ambry Genetics, GeneDx, Pathway Genetics, OMIM, Invitae and BIC); in the BIC database (46x with clinical importance, class 5 definitely pathogenic); in UMD (1x as a class 5 causal variant). In Clinvitae the variant was identified 5x as pathogenic The c.3048_3052dupTGAGA variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Asn1018MetfsX8 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1018 and leads to a premature stop codon 8 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at