17-43093844-G-A
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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.1687C>T(p.Gln563Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.44
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 17-43093844-G-A is Pathogenic according to our data. Variant chr17-43093844-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37426.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093844-G-A is described in Lovd as [Pathogenic]. Variant chr17-43093844-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.1687C>T | p.Gln563Ter | stop_gained | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.1687C>T | p.Gln563Ter | stop_gained | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:54Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:21Other:1
| 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 | Baylor Genetics | Jan 25, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1687C>T;p.(Gln563*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 12393792) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37426; PMID: 23199084; PMID: 24312913; PMID: 21989927; PMID: 25330149; PMID: 25948282; PMID: 26852130; PMID: 12393792) - PS4. The variant is present at low allele frequencies population databases (rs80356898 – gnomAD 0.0002795%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| 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 | All of Us Research Program, National Institutes of Health | Jan 04, 2024 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 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. - |
| not provided, no classification provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 13, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS3, PS4_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 26, 2023 | _x000D_ Criteria applied: PVS1, PS4 - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Mar 30, 2022 | - - |
| 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 | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Institute of Genomics, University of Tartu | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 06, 2021 | ACMG classification criteria: PVS1 very strong, PVS1, PS3 supporting, PS4 strong, PS4, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Sep 07, 2023 | ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2020 | Nonsense 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 (Janavicius 2010, Ghiorzo 2012, Karami 2013, Meisel 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 1806C>T; This variant is associated with the following publications: (PMID: 24312913, 15024741, 15876480, 20373018, 21989927, 22776961, 24504028, 12566964, 11504767, 9663595, 23397983, 25948282, 26852130, 25525159, 18439106, 26843898, 27003155, 27376475, 27425403, 27194814, 7837387, 27914478, 27741520, 27836010, 28123851, 28127413, 28166811, 28281021, 28324225, 26681312, 28857155, 29339979, 29335924, 29907814, 29346284, 11251181, 29161300, 30103829, 30606148, 29446198, 30720243, 30322717, 31589614, 32341426, 33087929, 23199084) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| 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 | Revvity Omics, Revvity | Jul 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 26, 2019 | The BRCA1 c.1687C>T; p.Gln563Ter variant (rs80356898), also known as 1806C>T, has been reported in multiple individuals with breast and/or ovarian cancer (Cunningham 2014, Maistro 2016, Shattuck-Eidens 1995, Wagner 1998). It is listed as pathogenic in ClinVar (Variation ID: 37426), and observed 6 times in the Genome Aggregation Database population database (6/245302 alleles). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Maistro S et al. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer. 2016; 16(1):934. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995; 273(7):535-41. Wagner T et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer. 1998; 77(3):354-60. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| 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 | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 21, 2019 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in patients with breast, ovarian and pancreatic cancers (PMID: 29335924 (2018), 28324225 (2017), 27741520 (2016), 26350514 (2015), 24312913 (2013), 21989927 (2012), 23199084 (2010)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 08, 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 08, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Gln563* variant was identified in 13 of 4212 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer and was present in 1 of 2600 control chromosomes (frequency: 0.0004) from healthy individuals (Alemar 2016, Cybulski 2015, Fernandes 2016, Jakimovska 2018, Kluska 2015, Maistro 2016, Meisel 2017). The variant was also identified in dbSNP (ID: rs80356898) as "With Pathogenic allele", ClinVar (classified as pathogenic by 23 submitters), LOVD 3.0 (49x as pathogenic), and UMD-LSDB (12x as causal). The variant was identified in control databases in 6 of 245302 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 111186 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In addition, one study demonstrated that this variant results in nonsense-mediated decay (Perrin-Vidoz 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Gln563*) 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 (rs80356898, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 21989927, 23199084, 24312913, 25330149, 25948282, 26852130). This variant is also known as 1806C>T. ClinVar contains an entry for this variant (Variation ID: 37426). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2017 | Variant summary: The BRCA1 c.1687C>T (p.Gln563X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/121138 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). These occurrences need to be cautiously considered due to the cohort could harbor individuals with a BRCA1 phenotype. This variant has been reported in multiple HBOC patients and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Gln563X variant in BRCA1 (also referred to as 1806C>T) has been reported in >100 individuals with BRCA1-associated cancers (Shattuck-Eidens 1995, Wagner 1998, Pohlreich 2003, Foretova 2004, Salazar 2006, Krajc 2008, Janav 2010, Zuradelli 2010, Blay 2013, Cunningham 2014, Kluska 2015, Cini 2016, Breast Cancer Information Core (BIC) database). It was also identified in 5/66568 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356898); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 563, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in HBOC. Furthermore, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282262.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. PVS1, PM2, PS4. - |
| Pathogenic, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 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 26, 2022 | The p.Q563* pathogenic mutation (also known as c.1687C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in numerous patients and families with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Ghiorzo P et al. Fam. Cancer. 2012 Mar;11:41-7; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Finch A et al. Clin. Genet. 2016 Mar;89:304-11; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Cotrim DP et al. BMC Cancer. 2019 Jan;19(1):4). This alteration has been described as a European founder mutation, having been detected in Austrian, Slovenian, Swedish and Polish populations (Janaviius R. EPMA J. 2010 Sep;1:397-412; Kluska A et al. BMC Med. Genomics. 2015 May;8:19). Of note, this alteration is also designated as 1806C>T 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 | curation | Sema4, Sema4 | May 21, 2021 | - - |
Breast and/or ovarian cancer Pathogenic:2
| 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 | May 13, 2016 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Nov 23, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. - |
Breast carcinoma;C0919267:Ovarian neoplasm Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 17, 2014 | - - |
Ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jul 01, 2016 | - - |
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 | Oct 31, 2018 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2023 | The BRCA1 c.1687C>T variant is predicted to result in premature protein termination (p.Gln563*). This variant (also known as c.1806C>T in the literature) has been reported to be causative for breast, ovarian, and pancreatic cancer (Shattuck-Eidens et al. 1995. PubMed ID: 7837387; Susswein et al. 2016. PubMed ID: 26681312, Table S1; Ghiorzo et al. 2012. PubMed ID: 21989927; Schrader et al. 2012. PubMed ID: 22776961). This variant is reported in 0.0062% 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/37426/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Computational scores
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Name
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at