17-43057062-T-TG
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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.5266_5267insC(p.Gln1756ProfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,912 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 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000069 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.46
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 17-43057062-T-TG is Pathogenic according to our data. Variant chr17-43057062-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 17677.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5266_5267insC | p.Gln1756ProfsTer74 | frameshift_variant | 19/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5266_5267insC | p.Gln1756ProfsTer74 | frameshift_variant | 19/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000183 AC: 46AN: 251494Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135922
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GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461732Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62AN XY: 727176
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GnomAD4 genome 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:77Uncertain:1Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:37
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jan 28, 2022 | The c.5266dup (p.Gln1756ProfsTer74) variant identified in the BRCA1 gene is the duplication of a single nucleotide resulting in a frameshift at amino acid 1756/1863 (exon 19/23). This variant is predicted to incorporate a premature termination codon at approximately 74 amino acids downstream and result in either loss-of-function via nonsense mediated decay or protein truncation. This variant is found with low frequency in gnomAD(v3.1.2) (8 heterozygotes, 0 homozygotes; allele frequency: 1.972e-5), suggesting it is not a common benign variant in the populations represented in that database. The c.5266dup (p.Gln1756ProfsTer74) variant is reported in ClinVar as Pathogenic by an expert panel (VarID: 17677), and is one of the most frequently reported pathogenic variants in the BRCA1 gene. This variant has been reported in multiple affected individuals in the literature [PMID: 21119707, 24797986, 31706072, others]. Based on the available evidence c.5266dup(p.Gln1756ProfsTer74) variant is reported as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 07, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2008 | - - |
| Pathogenic, no assertion criteria provided | research | Medical Genetics, Medical University Pleven | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | The c.5266dup (p.Gln1756Profs*74) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 7894492, 26718727, 20569256, 21503673, 23232912, 26666763, 22430266, 19359128, 20730485, 22032251, 21324516, among others, referred as 5382C in some publications], pancreatic cancer [PMID 24737347, 26440929] and prostate cancer [PMID 27433846 ]. This variant is a founder mutation in the Ashkenazi Jewish population and is found with a high prevalence in Poland and Eastern Europe [PMID 20569256, 20345474, 20507347]. The estimated risk for carriers of this variant was 89% for breast cancer and 42% for ovarian cancer by age 70 [PMID 22430266]. This one bp duplication in exon 19 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has been detected in 19 individuals from the ExAC database (http://exac.broadinstitute.org/variant/17-41209079-T-TG). This variant thus classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| 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 | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Feb 02, 2024 | ACMG Criteria: PM2_P; Variant was found in heterozygous state - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Apr 08, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 10, 2022 | DNA sequence analysis of the BRCA1 gene demonstrated a single base pair duplication in exon 19, c.5266dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 74 amino acids downstream of the change, p.Gln1756Profs*74. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.23% in the Ashkenazi Jewish subpopulation (dbSNP rs1217805587). This pathogenic sequence change is a well-described pathogenic BRCA1 variant and a known founder mutation in the Ashkenazi Jewish population reported in multiple individuals with hereditary breast and ovarian cancer syndrome (PMID: 12473589, 15131399, 9042909, 22430266, 24764757, 26976419). The c.5266dup sequence change is also referred to as 5382insC in the scientific literature - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| 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 | Institute of Genomics, University of Tartu | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 29, 2021 | This BRCA1 variant (rs80357906) is rare (<0.1%) in a large population dataset (gnomAD: 51/282892 total alleles, 0.018%, no homozygotes) and has been reported in ClinVar. This frameshift variant results in a premature stop codon in exon 19 of 23 likely leading to nonsense-mediated decay and lack of protein production. This variant, also known as 5382insC and 5385insC in the literature, is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population and has been reported in individuals from other ethnicities. This variant has been associated with a 67% to 89% risk of breast cancer by age 70, and a 33% to 42% risk of ovarian cancer by age 70. This variant was also identified in the patient's mother (JHG1740-2). We consider c.5266dupC to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.5266dup;p.(Gln1756Profs*74) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17677; PMID: 15994883; PMID: 22430266) - PS4. The variant is present at low allele frequencies population databases (rs80357906 – gnomAD 0.001803%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Aug 04, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Mar 11, 2024 | The BRCA1 c.5266dup (p.Gln1756Profs*74) variant is one of the most common variants reported in Central and Eastern European families with high risk of breast and/or ovarian cancer (Janavicius R, PMID: 23199084). This variant causes a frameshift by inserting one nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant has been reported in the ClinVar database as a germline pathogenic variant by 10 submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 30, 2024 | Criteria applied: PVS1,PS4,PM5_STR - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 06, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS4_STR, BS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 13, 2022 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PP1 strong - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 10, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 18, 2023 | The BRCA1 c.5266dup (p.Gln1756ProfsTer74) variant, also referred to as c.5382insC or c.5382_5383insC, causes a shift in the translational reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been previously identified in individuals with breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer (PMID: 29335925; PMID: 29961768; PMID: 11802209; PMID: 29492181; PMID: 22430266). Further, this variant is one of three well-characterized founder variants in the Ashkenazi Jewish population, accounting for an estimated 26% of pathogenic variants detected in this population (GeneReviews PMID: 20301425). The highest frequency of this allele in the Genome Aggregation Database is 0.002314 in the Ashkenazi Jewish population (v2.1.1). This variant has been classified as pathogenic by >60 submitters in ClinVar, including a BRCA1 expert panel. Based on the available evidence, the c.5266dup (p.Gln1756ProfsTer74) variant is classified as pathogenic for hereditary breast and ovarian cancer. - |
not provided Pathogenic:15Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2020 | Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5382insC or 5385insC; This variant is associated with the following publications: (PMID: 25859162, 25849179, 27160020, 26843898, 26852130, 26833046, 27025497, 27062684, 26681312, 29790872, 26440929, 30067863, 31336956, 32854451, 24372583, 21119707, 26656232, 26083025, 25476495, 24528374, 25195694, 22032251, 7894492, 16168118, 27223485, 26779294, 27433846, 26666763, 26718727, 29478780, 27425403, 22009639, 20569256, 21503673, 23232912, 20345474, 22430266, 29335925, 28285342, 22535016, 29339979, 23954390, 29433453, 29335924, 29492181, 21834074, 24737347, 19359128, 27914478, 28324225, 22666503, 27989354, 29907814, 20730485, 28091860, 28503720, 26556299, 10464624, 28423363, 20507347, 22006311, 25980754, 21324516, 29310832, 30333958, 30159786, 29161300, 30606148, 30152102, 28049106, 28111427, 30186769, 29961768, 30322717, 31090900, 31159747, 30113427, 23199084, 8841191, 30676620, 30489631, 31454914, 12771565, 31528241, 27741520, 29625052, 26689913, 32058061, 31447099, 32039725) - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Jan 17, 2024 | This variant has been identified by standard clinical testing. female patient with metastatic breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 04, 2023 | The BRCA1 c.5266dup (p.Gln1756Profs*74) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature as a founder mutation in the Ashkenazi Jewish population and has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMIDs: 18694767 (2008), 19208665 (2009), 21119707 (2011), 30606148 (2019), 32438681 (2020), 35409996 (2022)), as well as prostate cancer (PMID: 36612302 (2023)). This variant has also been reported in affected and control individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). A functional study showed that this variant caused the complete loss of BRCA1 phosphopeptide binding activity (PMID: 15133502 (2004)). Based on the available information, this variant is classified as pathogenic. - |
| 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 | Oct 05, 2023 | The BRCA1 c.5266dup; p.Gln1756ProfsTer74 variant, also known as 5382insC, has been described in individuals and families with hereditary breast and ovarian cancer, peritoneal cancer, and pancreatic cancer and is a known pathogenic founder variant (Bogdanova 2010, Elsakov 2010, Heidemann 2012, Simard 1994, Uglanitsa 2010, Zhang 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 17677). It is found in the general population with an overall allele frequency of 0.02% (51/282892 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating 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. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] 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 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 78(4):373-6. PMID: 20345474. Heidemann S et al. Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. Breast Cancer Res Treat. 2012 134(3):1229-39. PMID: 22535016. Simard J et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet. 1994 8(4):392-8. PMID: 7894492. Uglanitsa N et al. The contribution of founder mutations in BRCA1 to breast cancer in Belarus. Clin Genet. 2010 78(4):377-80. PMID: 20507347. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 121(2):353-7. PMID: 21324516. - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 07, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 18, 2014 | - - |
| 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 | Mar 18, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 23, 2023 | PP5, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BRCA1: PVS1, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 01, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Gln1756Profs*74) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs397507247, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9042909, 22185575, 22430266). This variant is also known as 5382insC and 5385insC. ClinVar contains an entry for this variant (Variation ID: 17677). This variant has been associated with a 67% to 89% risk of breast cancer by age 70, and a 33% to 42% risk of ovarian cancer by age 70 (PMID: 15994883, 22430266). This variant disrupts a region of the BRCA1 protein in which other variant(s) (Deletion (Exon 23)) have been determined to be pathogenic (PMID: 18431737, 24825132, 25428789; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | Founder variant in Ashkenazi Jews; accounts for 26% of pathogenic variants in this population - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 23, 2022 | The p.Gln1756ProfsX74 variant in BRCA1 (also referred to as p.Gln1777fs) is a founder variant in the Ashkenazi Jewish population and has been reported in >1000 individuals with BRCA1-associated cancers (Abeliovich 1997 PMID: 9042909, Elwad 2011 PMID: 22185575, Breast Cancer Information Core (BIC) database). This variant has also been identified in 0.2% (24/103702) Ashkenazi Jewish and 0.02% (25/129200) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1756 and leads to a premature termination codon 74 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 hereditary breast and ovarian cancer (HBOC). Furthermore, the p.Gln1756ProfsX74 variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar ID 17677). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PVS1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 09, 2021 | This mutation is an insertion of one nucleotide (cytosine), resulting in a frameshift and the creation of a novel translational termination codon after 74 amino acid residues. The protein product thus produced is truncated and non-functional. This mutation has been described in the international bibliography (http://research.nhgri.nih.gov/projects/bic) and has been shown to be a founder mutation in a number of ethnic groups (PMID: 12142080). This mutation has been described in the mutation database ClinVar (Variation ID:17677). - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 02, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 22, 2016 | Variant summary: The BRCA1 c.5266dupC variant results in a frameshift, which alters the protein's amino acid sequence beginning at position 1756 and leads to a premature termination codon 73 amino acids downstream. It is predicted to cause a truncated or absent BRCA1 protein due to non-sense meditated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (such as c.5387C>A/p.Ser1796X, c.5417delC/Pro1806fsX28, etc). Mutation Taster predicts a damaging outcome for this variant, and functional studies have shown HR activity is significantly impaired by this variant (Bouwman_BRCA1_Cancer Discovery_2013). BRCA1 c.5266dupC was found in 19/121412 control chromosomes at a frequency of 0.0001565, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in hundreds of HBOC patients and is reported as a known common founder mutation in the literature. Additionally, this variant has been classified by multiple clinical labs and databases as pathogenic. Taken together, this variant was classified as disease variant/pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Familial cancer of breast Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 30, 2024 | Criteria applied: PVS1,PS4,PM5_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 03, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. - |
Breast and/or ovarian cancer Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 07, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 24, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 27, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This variant (also known as 5382insC and 5385insC) inserts 1 nucleotide in exon 19 of the BRCA1 gene, causing a frameshift and a premature translational stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the C-terminal BRCT domain. Experimental studies have shown that variant impacts BRCA1 function in homology-directed repair and subcellular localization assays (PMID: 14729053, 23867111). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.13-0.28% minor allele frequency (PMID: 8841191, 9145676, 11466700, 30152102). This variant has been reported in numerous individuals affected with breast and/or ovarian cancer (PMID: 7545954, 7894492, 8531967, 9042909, 9150153, 17922257, 18334730, 21643751, 22430266, 25418591, 29335925, 30480775, 30606148, 30975216). This variant is the most globally frequent, pathogenic BRCA1 variant and has been reported in diverse populations in Africa, America, Asia and Europe (PMID: 24312913). The risk of female breast cancer among carriers of this mutation is 67-89% by age 70, and the risk of ovarian cancer is 22-42% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has reported this variant in 97/60369 cases and 11/53450 controls with an estimated OR of 7.808 (95%CI 4.185 to 14.567) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000440). This variant has been identified in 51/282892 chromosomes (24/10370 Ashkenazi Jewish chromosomes and 25/129200 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2022 | The c.5266dupC (p.Q1756Pfs*74) alteration, located in exon 19 (coding exon 18) of the BRCA1 gene, consists of a duplication of C at position 5266, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 0.5% in this population, but has also been shown to occur at high frequency in many other European populations (Hartge, 1999; Hamel, 2011; Kluz, 2018). Cumulative female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated in the literature at 67% (range: 36-83%) and 33% (range: 8-50%), respectively (Antoniou, 2005). Of note, this mutation is also designated as 5382insC and 5385insC in the published literature. Based on the available evidence, this alteration is classified as pathogenic. - |
Ovarian neoplasm Pathogenic:2
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 29, 2014 | - - |
Punctate palmoplantar keratoderma type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics dept., Datar Cancer Genetics Limited, India | Jul 21, 2017 | - - |
Breast neoplasm Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | - | - - |
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 | Nov 22, 2021 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 26, 2024 | The BRCA1 c.5266dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln1756Profs*74). This variant (also described as 5382insC, 5385insC, or 5329dupC) has been reported in multiple individuals with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370; Bogdanova et al. 2010. PubMed ID: 20569256; Alemar et al. 2016. PubMed ID: 27425403; Azzollini et al. 2016. PubMed ID: 27062684; Hamel et al. 2011. PubMed ID: 21119707). It is a founder variant in the Ashkenazi Jewish population and is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17677/). Frameshift variants in BRCA1 are expected to be pathogenic. In summary, this variant is interpreted as pathogenic. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pancreatic cancer, susceptibility to Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Oct 15, 2008 | - - |
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