rs80357609
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3700_3704del(p.Val1234GlnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,882 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: 0.0000034 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.87
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 17-43091826-GTTTAC-G is Pathogenic according to our data. Variant chr17-43091826-GTTTAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 37542.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091826-GTTTAC-G is described in Lovd as [Pathogenic]. Variant chr17-43091826-GTTTAC-G is described in Lovd as [Pathogenic]. Variant chr17-43091826-GTTTAC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3700_3704del | p.Val1234GlnfsTer8 | 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.3700_3704del | p.Val1234GlnfsTer8 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461882Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 exome
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:39
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| 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 | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant deletes 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 3819del5 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 7606717, 8554067, 11389159, 11802209 , 18489799, 20727672, 21324516, 23479189, 24171766, 24010542, 25366421, 28205045, 29335924, 33670479, 34072659) and has been described as a recurrent or founder mutation in the Czech Republic, Germany, Poland, Kosovo and Russia (PMID: 22864640, 23199084, 26843898, 36171877, 36299383, 36367610, 37147448). This variant was found to segregate with breast and ovarian cancer affected members in one large pedigree (PMID: 8554067). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 10/60456 cases, 1/53460 controls; OR=8.843 (95%CI 1.132 to 69.082); p-value=0.013; Leiden Open Variation Database DB-ID BRCA1_001454. 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| 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 | Apr 10, 2024 | Criteria applied: PVS1,PS4,PM2_SUP - |
| 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, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Dec 15, 2015 | - - |
| 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 | MGZ Medical Genetics Center | Jul 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 03, 2016 | - - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 24, 2020 | This frameshift variant causes the premature termination of BRCA1 protein synthesis. In the published literature, it has been reported in patients with breast/ovarian cancer and is described as a common mutation in individuals with Polish ancestry (PMID: 29335924 (2018), 28205045 (2017), 26843898 (2016), 22535016 (2012), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 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 individuals with Hereditary Breast and Ovarian Cancer syndrome and described as a recurrent variant in Eastern European individuals (Foretova 2004, Foretova 2010, Schneegans 2012, de Juan Jimenez 2013, Ratajska 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 3695_3699delGTAAA, 3819_3823delGTAAA, and 3819del5; This variant is associated with the following publications: (PMID: 26843898, 25452441, 21324516, 7606717, 21503673, 22535016, 26083025, 10952777, 23479189, 15024741, 21348412, 27167707, 28205045, 25366421, 22160602, 27836010, 24171766, 29339979, 29335924, 28324225, 30322717, 31159747, 18097605, 30702160, 30078507, 31528241, 32719484, 32846166, 32341426, 31742824, 32295079, 34011307) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 15, 2014 | - - |
| 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 | Mayo Clinic Laboratories, Mayo Clinic | Feb 08, 2023 | PP1, PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | BRCA1: PVS1, PM2, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 21, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 01, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 13, 2017 | The p.Val1234fs variant in BRCA1 has been reported in >60 individuals with BRCA1 -associated cancers (Brozek 2011, Ratajska 2015, Breast Cancer Information Core (BIC)), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1234 and leads to a premature termination codon 8 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-appro ved ENIGMA expert panel (ClinVar SCV000282314.1). In summary, the p.Val1234fs va riant meets criteria to be classified as pathogenic for HBOC in an autosomal dom inant manner. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2017 | Variant summary: The c.3700_3704delGTAAA (p.Val1234Glnfs) variant in BRCA1 gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (~121382 and 246014 chrs tested). The variant of interest has been reported in multiple affected individuals and was shown to segregate with the disease within the family. Multiple reputable databases/clinical laboratories and published reports cited the variant as pathogenic. Taking together, the variant was classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Val1234Glnfs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15024741, 18489799, 21324516, 23479189, 24010542, 25066507). This variant is also known as 3819del5. ClinVar contains an entry for this variant (Variation ID: 37542). 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 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2021 | The c.3700_3704delGTAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 3700 to 3704, causing a translational frameshift with a predicted alternate stop codon (p.V1234Qfs*8). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Takahashi H et al. Cancer Res., 1995 Jul;55:2998-3002; Serova O et al. Am J Hum Genet, 1996 Jan;58:42-51; Górski B et al. Am J Hum Genet, 2000 Jun;66:1963-8; Bergthorsson JT et al. J Med Genet, 2001 Jun;38:361-8; Foretova L et al. Hum Mutat, 2004 Apr;23:397-8; Ratajska M et al. Oncol Rep, 2008 Jan;19:263-8; Machackova E et al. BMC Cancer, 2008 May;8:140; Iyevleva AG et al. Cancer Lett, 2010 Dec;298:258-63; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Heidemann S et al. Breast Cancer Res Treat, 2012 Aug;134:1229-39; Ledwo JK et al. BMC Cancer, 2013 Oct;13:510; de Juan Jiménez I et al. Fam Cancer, 2013 Dec;12:767-77; Janaviius R et al. Cancer Genet, 2014 May;207:195-205; Meisel C et al. Arch Gynecol Obstet, 2017 May;295:1227-1238; Park B et al. Breast Cancer Res Treat, 2017 May;163:139-150; Zidekova D et al. Neoplasma;65:309-315; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Jakimovska M et al. Breast Cancer Res Treat, 2018 Apr;168:745-753; Rechsteiner M et al. J. Cancer Res. Clin. Oncol., 2018 May;144:865-874; Kluz T et al. Hered Cancer Clin Pract, 2018 Mar;16:6; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Koczkowska M et al. Cancers (Basel), 2018 Nov;10; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Rogoa-Janiszewska E et al. Cancers (Basel), 2020 Aug;12; Yildiz Tacar S et al. Life Sci, 2020 Nov;261:118334; Zografos E et al. BMC Cancer, 2021 May;21:572). This mutation has also been reported in a case study of a 74-year old male patient with a metastasized combined adeno-neuroendocrine carcinomas (MANEC) of the small bowel (Quaas A et al. BMC Gastroenterol, 2018 May;18:75). Of note, this alteration is also designated as c.3700_3704del5, 3819del5, and "3820-3824 5bp deletion" 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 | Nov 01, 2023 | This variant deletes 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 3819del5 based on Breast Cancer Information Core (BIC) nomenclature. This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 7606717, 8554067, 11389159, 11802209 , 18489799, 20727672, 21324516, 23479189, 24171766, 24010542, 25366421, 28205045, 29335924, 33670479, 34072659) and has been described as a recurrent or founder mutation in the Czech Republic, Germany, Poland, Kosovo and Russia (PMID: 22864640, 23199084, 26843898, 36171877, 36299383, 36367610, 37147448). This variant was found to segregate with breast and ovarian cancer affected members in one large pedigree (PMID: 8554067). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 10/60456 cases, 1/53460 controls; OR=8.843 (95%CI 1.132 to 69.082); p-value=0.013; Leiden Open Variation Database DB-ID BRCA1_001454. 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. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 26, 2019 | The BRCA1 c.3700_3704del; p.Val1234fs variant (rs80357609), also known as 3819del5, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer, and is described as a recurrent BRCA1 variant in Eastern European individuals (Brozek 2011, Foretova 2004, Gorski 2000, Heramb 2018, Konstantopoulou 2014, Machackova 2008, Ratajska 2008, Takahashi 1995). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37542), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, 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 to be pathogenic. References: Brozek I et al. Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet. 2011 Aug;52(3):325-30. Foretova L et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr;23(4):397-8. Gorski B et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000 Jun;66(6):1963-8. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Konstantopoulou I et al. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families. Clin Genet. 2014 Jan;85(1):36-42. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Ratajska M et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008 Jan;19(1):263-8. Takahashi H et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res. 1995 Jul 15;55(14):2998-3002. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Abnormality of the ovary Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 16, 2021 | - - |
Ovarian carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 21, 2021 | high grade serous carcinoma - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 09, 2021 | This sequence change deletes 5 nucleotides in exon 11 of BRCA1 mRNA (c.3700_3704delGTAAA), causing a frameshift at codon 1234 and the creation of a premature translation stop signal 8 amino acid residues later p.(Val1234Glnfs*8). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This sequence change has been reported in the international literature in multiple families with Hereditary Breast and Ovarian Cancer syndrome and has been suggested to be a common BRCA1 variant in the Czech Republic (PMID: 15024741 ;22160602 ).This mutation has been described in the mutation database ClinVar (Variation ID: 37542). - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
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