17-43045767-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.5503C>T(p.Arg1835Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,874 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 (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.950
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 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
PP5
Variant 17-43045767-G-A is Pathogenic according to our data. Variant chr17-43045767-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55601.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045767-G-A is described in Lovd as [Pathogenic]. Variant chr17-43045767-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.5503C>T | p.Arg1835Ter | stop_gained | 23/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5503C>T | p.Arg1835Ter | stop_gained | 23/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251278Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
GnomAD3 exomes
AF:
AC:
3
AN:
251278
Hom.:
AF XY:
AC XY:
2
AN XY:
135822
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727242
GnomAD4 exome
AF:
AC:
20
AN:
1461874
Hom.:
Cov.:
32
AF XY:
AC XY:
9
AN XY:
727242
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:46Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:17Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| 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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 14, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| 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, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Sep 13, 2023 | This sequence change creates a premature translational stop signal (p.Arg1856*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs41293465, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and bladder cancer (PMID: 8554067, 10486320, 11802209, 16683254, 19949876, 23704984, 27553291). This variant is also known as 5622C>T. ClinVar contains an entry for this variant (Variation ID: 55601). Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798). 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 | Institute of Human Genetics, University of Leipzig Medical Center | Nov 23, 2023 | Criteria applied: PVS1,PS3,PM5_PTC - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant changes 1 nucleotide in exon 23 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 to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in more than twenty individuals affected with breast and/or ovarian cancer (PMID: 8554067, 9760198, 10505028, 11260866, 16644204, 16683254, 20104584, 20727672, 24504028, 24549055, 25682074, 26187060, 26541979, 27153395, 27553291, 28324225, 28423363, 28724667, 29339979, 29470806, 31209999) and has been identified in over 100 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 3/251278 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 20, 2015 | The heterozygous variant in the BRCA1 gene (c.5503C>T; p.Arg1835*)is considered pathogenic. This change results in a premature stop codon interrupting an important functional domain BRCT2 (PMID: 11739404) and premature truncation results in impaired function. This variant has been previously published in 2 individuals of Punjabi ethnicity and part of a cohort of unrelated Pakistani individuals with breast and ovarian cancer (PMID: 16998791), though the paper has no additional information on the phenotype of the affected individuals. This variant has also been seen in multiple affected individuals by other clinical labs (SCV000109430, SCV000145551, SCV000186917, SCV000210227, SCV000077033). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained c.5503C>T p.Arg1835Ter variant in BRCA1 has been reported has been reported previously in heterozygous state in patients with breast cancer and ovarian cancer Hasmad HN et al. 2016. The experimental studies have shown that this premature translational stop signal affects BRCA1 function Ye Q et al 2001. The p.Arg1835Ter variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submiters. The nucleotide change c.5503C>T in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2020 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in multiple individuals with breast and/or ovarian cancer in the published literature (PMID: 8554067 (1996), 16998791 (2006), 24504028 (2014), 27553291 (2016), 29021639 (2017), 28724667 (2017)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 17, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 28, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | BRCA1: PVS1, PM2, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2023 | Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Reported in association with hereditary breast and/or ovarian cancer (Serova et al., 1996; Meindl, 2002; Rashid et al., 2006; van der Hout et al., 2006; Borg et al., 2010; Cunningham et al., 2014; Kwong et al., 2016); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5622C>T; This variant is associated with the following publications: (PMID: 12360400, 24504028, 16998791, 29176636, 8554067, 25682074, 26541979, 25085752, 26898890, 26848529, 21559243, 17591843, 11260866, 9796975, 27767231, 25066507, 16683254, 27553291, 15026808, 29922827, 28888541, 34282142, 20727672, 26404129, 10505028, 18465347, 10486320, 26028024, 25722380, 27157322, 12601471, 12960223, 18375895, 11920621, 16782705, 12393792, 24578176, 9760198, 20104584, 24728189, 27194814, 23569316, 16644204, 11739404, 11802209, 9667259, 10699917, 16528604, 26976419, 24249303, 19949876, 23704984, 28324225, 29339979, 29752822, 29470806, 28724667, 28993434, 29310832, 30702160, 29446198, 31090900, 31528241, 30855176, 30291343, 32338768, 33758026, 35356428, 33804961, 35377489, 33087929, 30875412, 32710294, 32719484, 31825140, 33654310, 36988593, 30209399) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| 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 | Clinical Genetics and Genomics, Karolinska University Hospital | Apr 10, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 03, 2022 | DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.5503C>T, which results in the creation of a premature stop codon at amino acid position 1835, p.Arg1835*. This sequence change is reported in the gnomAD database with a global population frequency of 0.0012% (dbSNP rs41293465). This sequence change has been described in multiple individuals and families with breast, ovarian and bladder cancer (PMID: 27553291, 8554067, 10486320,11802209, 16683254,19949876, 23704984,31528241). Of note, this alteration is also designated as 5622C>T in published literature. Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798). These collective evidences indicate that this sequence change is pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 28, 2020 | Variant summary: BRCA1 c.5503C>T (p.Arg1835X) 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 allele was found at a frequency of 1.2e-05 in 251278 control chromosomes. c.5503C>T has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 08, 2019 | The p.Arg1835X variant in BRCA1 has been identified in >50 individuals with BRCA1-associated cancers (Breast Cancer Information Core (BIC) database). This variant has been identified in 2/30616 South Asian chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); 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 1835. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD), resulting in a truncated protein. However, in vitro functional studies provide some evidence that this truncation may impact protein function (Ye 2001). Furthermore, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000282345.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC) based upon its frequency in affected individuals and absence from controls. ACMG/AMP Criteria applied: PVS1_Strong, PS4, PS3_Supporting, PM2. - |
| 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.Arg1835*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs41293465, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and bladder cancer (PMID: 8554067, 10486320, 11802209, 16683254, 19949876, 23704984, 27553291). This variant is also known as 5622C>T. ClinVar contains an entry for this variant (Variation ID: 55601). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 11739404). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 12400015, 21922593; 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, no assertion criteria provided | clinical testing | Cancer Genomics Lab, PINUM Cancer Hospital | Feb 20, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2022 | The p.R1835* pathogenic mutation (also known as c.5503C>T), located in coding exon 22 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5503. This changes the amino acid from an arginine to a stop codon within coding exon 22. This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Rashid MU et al. BMC Cancer. 2016 08;16:673; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48:58-63; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Apessos A et al. Cancer Genet. 2018 01;220:1-12). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as 5622C>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 07, 2023 | This variant changes 1 nucleotide in exon 23 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 to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in more than twenty individuals affected with breast and/or ovarian cancer (PMID: 8554067, 9760198, 10505028, 11260866, 16644204, 16683254, 20104584, 20727672, 24504028, 24549055, 25682074, 26187060, 26541979, 27153395, 27553291, 28324225, 28423363, 28724667, 29339979, 29470806, 31209999) and has been identified in over 100 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 3/251278 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 | curation | Sema4, Sema4 | Dec 08, 2020 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 14, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 21, 2015 | - - |
Lung cancer;C0346153:Familial cancer of breast;C0919267:Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Breast neoplasm Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single amino acid change from Arginine to a termination codon at amino acid residue 1835 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be 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 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 08, 2021 | - - |
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 | Sep 29, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg1835X variant is reported in the literature in 12/7062 proband chromosomes of individuals with breast and ovarian cancer (Bellacosa 2010, Borg 2010, Dizin 2006, Evans 2003, Ferla 2007, Frank 1998, Magnard 2002, Ramus 2007, Rashid 2006, Spurdle 2008); it was not found in any of the 484 control chromosomes. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs#:41293465) but no frequency information was provided, and is therefore, not very informative for assessing the population frequency. The alteration leads to a premature stop codon at position 1835 which is predicted to lead to a truncated or absent protein and loss of function, which is an established disease mechanism for the BRCA1 gene in hereditary breast and ovarian cancer. The variant is reported in the BIC database (x66) and UMD database (x20) as a variant of clinical significance. In addition, two functional studies using the yeast two-hybrid screen and glutathione-S-transferase (GST) pull-down assay, determined that the variant abolished interaction of BRCA1 with two proteins: Acetyl Coenzyme A (CoA) Carboxylase and PABP (Dizin 2006, Magnard 2002). In summary, based on the above information, this variant is 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
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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