rs80357223
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2800C>T(p.Gln934*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,808 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: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.52
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43092731-G-A is Pathogenic according to our data. Variant chr17-43092731-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54683.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092731-G-A is described in Lovd as [Pathogenic]. Variant chr17-43092731-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461808Hom.: 0 Cov.: 49 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 exome
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49
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727198
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
| 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 13, 2011 | - - |
| 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 | Baylor Genetics | Dec 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Research Institute, Aichi Cancer Center | Feb 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2020 | Variant summary: BRCA1 c.2800C>T (p.Gln934X) 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. The variant was absent in 251150 control chromosomes (gnomAD). c.2800C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018) mainly occurring in the Japanese population, where it appeared to be a founder mutation (Sekine_2001). These data indicate that the variant is very likely to be associated with disease. Nine other ClinVar submitters (evaluation after 2014) including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 04, 2024 | This sequence change creates a premature translational stop signal (p.Gln934*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 10804288, 11149425, 11595708, 18159056, 19016756, 25802882). It is commonly reported in individuals of Japanese ancestry (PMID: 10804288, 11149425, 11595708, 18159056, 19016756, 25802882). This variant is also known as 2919C>T. ClinVar contains an entry for this variant (Variation ID: 54683). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Mar 18, 2019 | - - |
| 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 | GeneDx | Sep 22, 2016 | This variant is denoted BRCA1 c.2800C>T at the cDNA level and p.Gln934Ter (Q934X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA1 2919C>T using alternate nomenclature, has been published as a Japanese pathogenic founder variant and has been observed in several breast and/or ovarian cancer families (Kashima 2000, Sekine 2001, Sugano 2008, Hirotsu 2015, Sakamoto 2016). We consider it to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2022 | The p.Q934* pathogenic mutation (also known as c.2800C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2800. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been described in multiple individuals and families with personal and/or family history consistent with hereditary breast and ovarian cancer syndrome (Ikeda N et al. Int. J. Cancer, 2001 Jan;91:83-8; Sekine M et al. Clin. Cancer Res., 2001 Oct;7:3144-50; John EM et al. JAMA, 2007 Dec;298:2869-76; Sugano K et al. Cancer Sci., 2008 Oct;99:1967-76; Hirotsu Y et al. Mol Genet Genomic Med, 2015 Mar;3:121-9; Hirasawa A et al. Oncotarget. 2017 Dec;8(68):112258-112267; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). This alteration has been described as a Japanese founder mutation (Sekine M et al. Clin. Cancer Res., 2001 Oct;7:3144-50; Karami F et al. Biomed Res Int, 2013 Nov;2013:928562). Of note, this alteration is also designated as 2919C>T in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Ovarian carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 12, 2021 | - - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Gln934X variant was identified in 18 of 6044 proband chromosomes (frequency: 0.003) from individuals or families with breast and ovarian cancer (Arai 2018, Hirotsu 2014, Ikeda 2001, John 2007, Sekine 2001, Sugano 2008). The variant was also identified in the following databases: dbSNP (ID: rs80357223) as "With Pathogenic allele", ClinVar (7x pathogenic including review by exper panel ENIGMA), Clinvitae (4x pathogenic), LOVD 3.0 (12x), UMD-LSDB (3x causal), BIC Database (4x pathogenic), and ARUP Laboratories (definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant has been suggested to be a founder mutation in the Japanese population (Sekine 2001). The c.2800C>T variant leads to a premature stop codon at position 934 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 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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