rs80357711
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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.4035del(p.Glu1346LysfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,396 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: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.773
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 17-43091495-CT-C is Pathogenic according to our data. Variant chr17-43091495-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37560.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091495-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43091495-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4035del | p.Glu1346LysfsTer20 | 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.4035del | p.Glu1346LysfsTer20 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251112Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135720
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461168Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6AN XY: 726812
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GnomAD4 genome 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
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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:17
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 15, 2023 | Criteria applied: PVS1,PS4,PM5_STR - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Apr 19, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 08, 2023 | This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4153delA and 4154delA in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with breast and ovarian cancer (PMID: 20345474, 24770866, 29785153, 30040829) and is known to be a founder mutation in the Baltic Population (PMID: 23274591). This variant also has been detected in a breast cancer case-control meta-analysis in 11/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000791). This variant has been identified in 12/282514 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, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Glu1346LysfsX20 deletion variant was identified in 176 of 22934 proband chromosomes (frequency: 0.008) from individuals with prostate cancer, breast cancer, ovarian cancer, or other gynaecological tumours, and was present in 3 of 11336 control chromosomes (frequency: 0.0003) (Bayraktar 2012, Bogdanova 2010, Cybulski 2013, Elsakov 2010, Gayther 1996 8644703, Jakubowska 2008, Plakhins 2011, Tikhomirova 2005, Uglanitsa 2010). The variant is described in the literature as a founder mutation in Slavic and Baltic countries, including Poland, Belarus, Latvia, Russia, and Lithuania (Bogdanova 2010, Cybulski 2013, Elsakov 2010, Ozolina 2009, Uglanitsa 2010). The variant was also identified in dbSNP (ID: rs80357711) “With pathogenic allele”, HGMD, UMD (2X as a causal variant), and the BIC database (51X as a variant with clinical importance). The p.Glu1346LysfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1346 and leads to a premature stop codon 20 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. - |
| 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 | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | Institute of Genomics, University of Tartu | - | - - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 19, 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 | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 04, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 14, 2022 | - - |
| 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, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2022 | 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 a personal or family history consistent with pathogenic variants in this gene and is reported as a pathogenic founder variant in several eastern European countries (Gayther 1996, Bogdanova 2010, Janavicius 2013, Szwiec 2015, Synowiec 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4153delA or 4154delA; This variant is associated with the following publications: (PMID: 29684080, 29339979, 8644703, 26779294, 23274591, 26928677, 29492181, 28166811, 23149842, 22032251, 22009639, 20345474, 20507347, 20569256, 24504028, 24797986, 20223023, 24528374, 26753012, 26843898, 27836010, 26681312, 29723101, 28831036, 29719582, 29785153, 29086229, 28279176, 30720243, 30322717, 31159747, 29625052, 26689913, 27535533) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 29, 2020 | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Mar 06, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Oct 16, 2024 | This variant has been identified by standard clinical testing. female patient with triple negative breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 12, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | BRCA1: PVS1, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 26, 2021 | The BRCA1 c.4035delA; p.Glu1346LysfsTer20 variant (rs80357711), also known as 4153del or 4154del, is reported in several individuals affected with breast and ovarian cancer and is described as a pathogenic founder variant in the European population (Bogdanova 2010, Elsakov 2010, Plakhins 2011). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37560) and is listed in the non-Finnish European population with an allele frequency of 0.009% (12/129,020 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, 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: Bogdanova NV et al. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet. 2010 Oct;78(4):364-72. PMID: 20569256. Elsakov P et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010 Oct;78(4):373-6. PMID: 20345474. Plakhins G et al. Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia. BMC Med Genet. 2011 Oct 27;12:147. PMID: 22032251. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2022 | Variant summary: BRCA1 c.4035delA (p.Glu1346LysfsX20) 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 allele was found at a frequency of 2.8e-05 in 253150 control chromosomes. c.4035delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Gorski_2004, Bogdanova_2010, 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. 21 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 | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| 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 | Jul 26, 2019 | The p.Glu1346LysfsX20 variant in BRCA1 has been reported in >100 individuals with BRCA1-associated cancers and is a known eastern European founder mutation (Janavicius 2013, Tihomirova 2014, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has been identified in 12/129020 (0.009%) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Morevoer, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282321.1). In summary, the p.Glu1346LysfsX20 variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Glu1346Lysfs*20) 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 (rs80357711, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15591272, 20345474, 20569256, 22032251, 23199084). This variant is also known as 4153delA and 4154delA. ClinVar contains an entry for this variant (Variation ID: 37560). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2024 | This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4153delA and 4154delA in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with breast and ovarian cancer (PMID: 20345474, 24770866, 29785153, 30040829) and is known to be a founder mutation in the Baltic Population (PMID: 23274591). This variant also has been detected in a breast cancer case-control meta-analysis in 11/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000791). This variant has been identified in 12/282514 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 | Ambry Genetics | May 05, 2022 | The c.4035delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4035, causing a translational frameshift with a predicted alternate stop codon (p.E1346Kfs*20). This mutation has been reported in numerous cases of breast and ovarian cancer (Gayther SA et al. Am. J. Hum. Genet. 1996 Mar;58:451-6; Elsakov P et al. Clin. Genet. 2010 Oct;78:373-6; Uglanitsa N et al. Clin. Genet. 2010 Oct;78:377-80; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Maxwell KN et al. Nat. Commun. 2017 08;8:319; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Yehia L et al. PLoS Genet., 2018 04;14:e1007352; Kowalik A et al. PLoS ONE, 2018 Jul;13:e0201086; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165). Furthermore, this mutation is regarded as a founder mutation of Baltic origin, with the highest observed frequency in Lithuania (Janavicius R et al. Eur. J. Med. Genet. 2013 Mar;56:125-30). Of note, this alteration is also designated as 4154delA and 4153delA 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 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 20, 2023 | _x000D_ Criteria applied: PVS1, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 09, 2021 | This sequence change deletes 1 nucleotide from exon 11 of the BRCA1 mRNA (c.4035delA), causing a frameshift after codon 1346 and the creation of a premature translational stop signal 20 amino acid residues later (p.Glu1346Lysfs*20) This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This variant is also known as 4153delA and 4154delA in the international literature and is a known common cause of breast and ovarian cancer in individuals from Eastern Europe (PMID: 22032251 ,23199084).This mutation has been described in the mutation database ClinVar (Variation ID: 37560). - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 20, 2024 | The BRCA1 c.4035delA variant is predicted to result in a frameshift and premature protein termination (p.Glu1346Lysfs*20). This variant has been reported multiple times as a founder variant in Belarus, Lithuania, and neighboring countries in families with hereditary breast and ovarian cancer (Gayther et al. 1996. PubMed ID: 8644703; Boqdanova et al. 2010. PubMed ID: 20569256, reported as 4153delA or 4154delA; Elsakov et al. 2010. PubMed ID: 20345474; Uqlanitsa et al. 2010. PubMed ID: 20507347). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37560/?new_evidence=true). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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