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rs431825413

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007294(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 0.0000526 in 152180 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1756Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

BRCA1
NM_007294 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:71U:1O:3

Conservation

PhyloP100: 2.46

Links

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 UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5266_5267insC p.Gln1756ProfsTer74 frameshift_variant 19/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5266_5267insC p.Gln1756ProfsTer74 frameshift_variant 19/231 NM_007294.4 P2P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152180
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000183
AC:
46
AN:
251494
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00238
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000691
AC:
101
AN:
1461732
Hom.:
0
AF XY:
0.0000853
AC XY:
62
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00119
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000540
Gnomad4 OTH exome
AF:
0.000149
Alfa
AF:
0.000400
Hom.:
0
Bravo
AF:
0.0000340
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:71Uncertain:1Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:32
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineMay 25, 2017The 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 submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 10, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 04, 2023Criteria applied: PVS1,PS4 -
Pathogenic, criteria provided, single submitterclinical testingBiomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar-- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityOct 29, 2021This 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, no assertion criteria providedliterature onlyOMIMOct 15, 2008- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genetics Bochum, Ruhr University BochumAug 04, 2022ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -
Pathogenic, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Apr 22, 2016Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria providedclinical testingDivision of Human Genetics, Medical University InnsbruckFeb 11, 2015- -
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Medical Genetics, Oslo University HospitalJul 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterSep 06, 2022- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterresearchInstitute of Genomics, University of Tartu-- -
Pathogenic, criteria provided, single submitterliterature onlyCounsylJul 07, 2014- -
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022The 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 providedclinical testingBRCAlab, Lund UniversityAug 26, 2022- -
Pathogenic, criteria provided, single submitterresearchCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 09, 2022PVS1, PS4_STR, BS1 -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterJan 28, 2022The 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, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyAug 23, 2021- -
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 18, 2023The 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. -
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Apr 08, 2014- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyDec 10, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenologica MedicaJan 01, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 13, 2022ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PP1 strong -
Pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoJan 10, 2022DNA 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 submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaApr 02, 2020- -
Pathogenic, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
not provided Pathogenic:14Other:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 07, 2014- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 30, 2021The BRCA1 c.5266dupC; p.Gln1756ProfsTer74 variant (rs80357906), 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. 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. 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. 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. Simard J et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet. 1994 8(4):392-8. Uglanitsa N et al. The contribution of founder mutations in BRCA1 to breast cancer in Belarus. Clin Genet. 2010 78(4):377-80. 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. -
not provided, no assertion providedphenotyping onlyGenomeConnect, 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, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicDec 14, 2020- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Karolinska University Hospital, Karolinska University HospitalSep 18, 2014- -
Pathogenic, criteria provided, single submitterclinical testingPerkinElmer GenomicsJul 14, 2022- -
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, PreventionGeneticsOct 31, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 20, 2019This frameshift variant causes the premature termination of BRCA1 protein synthesis. It has also been reported as pathogenic and as a known founder mutation in the Ashkenazi Jewish population (PMIDs: 18694767 (2008), 19208665 (2009), and 21119707 (2011)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 12, 2020Frameshift 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) -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023Criteria applied: PVS1, PS4:Moderate -
Hereditary breast ovarian cancer syndrome Pathogenic:9Other:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 03, 2022This sequence change creates a premature translational stop signal (p.Gln1756Profs*74) 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 (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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 22, 2016Variant 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, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioFeb 02, 2017- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 24, 2019The 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, Elwad 2011, Breast Cancer Information Core (BIC) database). This variant has also been identified in 24/103702 Ashkenazi Jewish and 25/129200 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397507247). 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.Gln1756fs variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282341.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in affected individuals. ACMG/AMP Criteria applied: PS4, PVS1. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Feb 14, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 09, 2021This 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 submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateNov 16, 2021- -
not provided, no assertion providedliterature onlyGeneReviews-Founder variant in Ashkenazi Jews; accounts for 26% of pathogenic variants in this population -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Familial cancer of breast Pathogenic:4
Pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 20, 2023Criteria applied: PVS1,PS4,PS3_MOD -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 03, 2019This 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 providedclinical testingFoulkes Cancer Genetics LDI, Lady Davis Institute for Medical ResearchJul 07, 2016- -
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumJun 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMar 10, 2022- -
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingTrue Health DiagnosticsApr 27, 2018- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 07, 2021The c.5266dupC pathogenic mutation, located in coding exon 18 of the BRCA1 gene, results from a duplication of C at nucleotide position 5266, causing a translational frameshift with a predicted alternate stop codon (p.Q1756Pfs*74). 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 P et al. Am. J. Hum. Genet. 1999 Apr;64:963-70; Hamel N et al. Eur. J. Hum. Genet. 2011 Mar;19:300-6; Kluz T et al. Hered Cancer Clin Pract. 2018 Feb;16:6). This mutation has been reported in individuals with hereditary breast and ovarian cancer (HBOC) syndrome, including individuals with male breast cancer, pancreatic cancer, and prostate cancer (Antoniou AC et al. J. Med. Genet. 2005 Jul;42:602-3; Bogdanova NV et al. Clin. Genet. 2010 Oct;78(4):364-72; Finkelman BS et al J Clin Oncol. 2012 Apr;30(12):1321-8; Bernards SS et al. Gynecol Oncol. 2016 Feb;140(2):221-5; Pritchard CC et al. N Engl J Med. 2016 Aug;375(5):443-53; Kluz T et al. Hered Cancer Clin Pract. 2018 Mar;16:6; Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Yurgelun MB et al. Genet Med. 2019 Jan;21(1):213-223). In a large case control-study, this variant was reported in 97/60,466 breast cancer cases and in 11/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 5382insC and 5385insC in the 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 17, 2021This 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. An experimental study has shown that the mutant protein carrying this variant is unable to form nuclear foci, even when targeted to the nucleus by BARD1, and accumulates in the cytoplasm (PMID: 14729053). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.13-0.28% minor allele frequency (PMID: 30152102). This variant has been reported in numerous individuals affected with breast and ovarian cancer (PMID: 7545954, 7894492, 8531967, 9042909, 9150153, 21643751, 22430266, 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). 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. -
Neoplasm of ovary Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaMay 29, 2014- -
Pathogenic, no assertion criteria providedresearchGerman Consortium for Hereditary Breast and Ovarian Cancer, University Hospital CologneDec 01, 2018- -
Punctate palmoplantar keratoderma type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBioinformatics dept., Datar Cancer Genetics Limited, IndiaJul 21, 2017- -
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitterresearchA.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 submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 22, 2021- -
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumFeb 21, 2023- -
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Pancreatic cancer, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMOct 15, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80357906; hg19: chr17-41209079;