17-43093459-CTT-CT
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2071delA(p.Arg691fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,742 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.831
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]
Genome browser will be placed here
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 17-43093459-CT-C is Pathogenic according to our data. Variant chr17-43093459-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37444.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093459-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093459-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2071delA | p.Arg691fs | frameshift_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.2071delA | p.Arg691fs | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461742Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727166
GnomAD4 exome
AF:
AC:
5
AN:
1461742
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
727166
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:27
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 25, 2022 | The BRCA1 c.2071del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) BRCA1:c.2071del is a deletion of a single nucleotide in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 10 of the frame-shift, or 701 (BRCA1 p.(Arg691AspfsTer10):) using NP_009225.1. This is expected to result in disrupted or absent protein product due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun et al., 2018 PMID:30192042). BRCA1:c.2071del (rs80357688) is absent in population databases (gnomAD) and is not on record in FLOSSIES. BRCA1:c.2071del (also described as BRCA1 2190delA using legacy nomenclature) has been reported in multiple unrelated individuals with breast and/or ovarian cancer (Zhang et al., 2011 PMID: 21324516, Cunningham et al., 2014 PMID: 24504028, Ow et al., 2019 PMID: 30875412, George et al., 2021 PMID: 33646313). BRCA1:c.2071del is on record in ClinVar (Variation ID: CD982486) reported by multiple clinical laboratories as pathogenic in association with Hereditary breast and ovarian cancer. This variant is listed in HGMD as ‘disease causing mutation’ in association with Breast cancer (Accession: CD982486). - |
| 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 | Nov 06, 2023 | This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics dept., Datar Cancer Genetics Limited, India | Jul 07, 2017 | - - |
| 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 | Genetic Services Laboratory, University of Chicago | May 22, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 18, 2015 | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 07, 2020 | This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in symptomatic individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9482581 (1998), 21324516 (2011), 24504028 (2014), and 26287763 (2015)). 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, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Arg691AspfsX10 deletion variant was identified in 7 of 9116 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, or prostate cancer (Castro 2013, Gayther 1999, Jongsma 2002, Risch 2001, Kurian 2008, Zhang 2011). The variant was also identified in dbSNP (ID: rs80357688) “With pathogenic allele”, HGMD, UMD (1X as a causal variant), and the BIC database (24X with clinical importance). The p.Arg691AspfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 691 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; 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 2190delA; This variant is associated with the following publications: (PMID: 21324516, 10486320, 24728189, 23942203, 19471317, 9482581, 17148771, 23569316, 26287763, 24504028, 25371446, 25452441, 23458327, 25556971, 11437066, 17369502, 27534398, 28127413, 33646313, 30875412, 24950059, 34347777, 31897316, 35186721, 27533253, 24830819, 26295337, 33758026) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 15, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 14, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg691Aspfs*10) 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 family history of breast and/or ovarian cancer (PMID: 9482581, 9667259, 10486320, 21324516, 24504028). This variant is also known as 2190delA. ClinVar contains an entry for this variant (Variation ID: 37444). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2017 | Variant summary: The BRCA1 c.2071delA (p.Arg691Aspfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2138C>G, p.Ser713X; c.2157dupA, p.Glu720fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121338 control chromosomes. This variant was reported in multiple patients with HBOC (Judkins_2005, Trujillano_2014, Peto_1999, Frank_1998, Risch_2001, Zhang_2011). In addition, 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 | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with a risk of breast and ovarian cancer (MIM#604370), fanconi anemia, complementation group S (MIM#617883) and other types of cancer (OMIM). (I). 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance of variants is associated with fanconi anaemia, complementation group S (MIM#617883), whilst autosomal dominant inheritance is associated with an increased risk for familial breast and/or ovarian cancer, 1 (MIM#604370), or pancreatic cancer susceptibility, 4 (MIM#614320). The gene has also been reported to be associated with increased risk for prostate and stomach cancer (PMID: 26236408). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2.1.1 and v3). (SP) 0701 - Other variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. Multiple frameshift and nonsense variants throughout the gene have been reported to be pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. ClinVar: Pathogenic x18 including a submission by an Expert Review panel. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 31, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Dec 01, 2009 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 07, 2023 | This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least 10 individuals affected with breast, ovarian, and fallopian tube cancer (PMID: 9482581, 9667259, 10359546, 11179017, 12354934, 17369502, 21324516, 23458327, 24240112, 24504028, 24728189, 25371446, 26287763, 30875412, 33646313) and an individual affected with prostate cancer (PMID: 23569316). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The c.2071delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2071, causing a translational frameshift with a predicted alternate stop codon (p.R691Dfs*10). This mutation has been observed in multiple breast and/or ovarian cancer families (Andersen TI et al. Hum. Mutat. 1998;11:166-74; Frank TS et al. J Clin Oncol, 1998 Jul;16:2417-25; Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Jongsma AP et al. Mol Pathol, 2002 Oct;55:305-9; Judkins T et al. Cancer Res, 2005 Nov;65:10096-103; Konecny M et al. Breast Cancer Res Treat. 2011 Feb;126:119-30; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Akbari MR et al. Clin. Genet. 2014 Jan;85:64-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Torres-Mejía G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Pal T et al. Cancer. 2015 Dec;121:4173-80) and in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 2190delA and 2187delA in the 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. - |
Fanconi anemia, complementation group S Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9482581, 24504028, 21324516] - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at