rs41293455
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.4327C>T(p.Arg1443Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,954 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 1.53
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 17-43082434-G-A is Pathogenic according to our data. Variant chr17-43082434-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17675.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082434-G-A is described in Lovd as [Pathogenic]. Variant chr17-43082434-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4327C>T | p.Arg1443Ter | stop_gained | 12/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4327C>T | p.Arg1443Ter | stop_gained | 12/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
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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:17
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
| 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2018 | This rare nonsense variant c.4327C>T (p.Arg1443*) in the BRCA1 gene is extremely rare in public databases and is predicted to introduce a premature translation termination codon. This variant is considered to be a founder mutation (PMID 15883839 ) and has been observed in multiple unrelated individuals with breast cancer (PMID 10422801,21324516, 7894491). Therefore, this c.4327C>T (p.Arg1443*) variant in the BRCA1 gene is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 14, 2013 | - - |
| 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 | Oct 23, 2023 | This variant changes 1 nucleotide in exon 12 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 at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 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 | literature only | Counsyl | Oct 02, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 29, 2016 | - - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 02, 2023 | PP5, PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 03, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Oct 17, 2023 | This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Not enough evidence - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| 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 | Aug 19, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 25, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 06, 2023 | The BRCA1 c.4327C>T (p.Arg1443*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 32885271 (2021), 32854451 (2020), 32341426 (2020), 32029870 (2020), 28724667 (2017)) and endometrial cancer (PMID: 28049106 (2017)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010). The frequency of this variant in the general population, 0.000085 (3/35428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2019 | 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4446C>T; This variant is associated with the following publications: (PMID: 23233716, 26028024, 25371446, 27463008, 28127413, 19656415, 9625424, 7493024, 8533757, 28111427, 29446198, 16905680, 25525159, 18680205, 23341105, 22401979, 15382066, 20694749, 15883839, 10090482, 23199084, 17148771, 11307153, 10486320, 7894491, 21324516, 27469594, 27184744, 27393621, 26541979, 28049106, 27783335, 16030099, 25236687, 27533253, 26976419, 21120943, 27221827, 26911350, 25504618, 17688236, 27286788, 25085752, 27553291, 28283652, 28392550, 19863560, 15726418, 25652403, 17591843, 19241424, 11179017, 17221156, 22798144, 9792861, 10682662, 26295337, 19329713, 16417652, 10422801, 15951958, 18821011, 10984458, 8990217, 21203900, 8571953, 28985766, 26681312, 28993434, 29907814, 29470806, 28724667, 30702160, 30630528, 30078507, 30720243, 30322717, 30093976, 31090900, 32467295, 33646313, 11597388, 31447099, 31825140, 32341426, 32885271, 30875412, 31742824, 33087929) - |
Hereditary breast ovarian cancer syndrome Pathogenic:6Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 04-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| 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 | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg1443*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16030099, 19656415, 22798144, 23233716). It is commonly reported in individuals of French Canadian ancestry (PMID: 10422801, 11250694, 15883839, 20694749). This variant is also known as 4446C>T. ClinVar contains an entry for this variant (Variation ID: 17675). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2023 | The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers and is considered to be a French-Canadian founder mutation (Vézina 2005 PMID:15883839, Hall 2009 PMID:19241424). It has also been identified in 0.002% (1/41432) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). 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 1443, which is predicted to lead to a truncated or absent protein. This is corroborated by a functional study that provides some evidence that this variant results in a truncated protein that lacks the BRCT domains (Caligo 2009 PMID:18680205). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 17675). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1_Strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2016 | Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2023 | This variant changes 1 nucleotide in exon 12 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 at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 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 | Nov 09, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2021 | The p.R1443* pathogenic mutation (also known as c.4327C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4327. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation is a well-known French Canadian founder mutation and has been reported in numerous breast and/or ovarian cancer families to date (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Ghadirian P et al. Clin. Genet. 2009 Nov;76(5):421-6; Janavicius R et al. EPMA J. 2010 Sep;1(3):397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). In addition to French Canadians, this mutation has also been identified in multiple other populations (McKean-Cowdin R et al. Hum. Genet. 2005 May;116(6):497-506; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159(1):131-8; Jalkh N et al. BMC Med Genomics 2017 Feb;10(1):8; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). Of note, this alteration is also designated as 4446C>T and R1443X in some 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. - |
not specified Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 21, 2019 | The BRCA1 c.4327C>T; p.Arg1443Ter variant (rs41293455), also known as 4446C>T for traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Castilla 1994, de Jonge 2017, Rashid 2016, Sun 2017, Susswein 2016, Zhang 2011). This variant is also described as a founder variant in the French Canadian population (Cavallone 2010, Neuhausen 2000, Tonin 1999, Vezina 2005). It is reported by multiple laboratories in ClinVar (Variation ID: 17675), and found in the general population with a low overall allele frequency of 0.002% (6/246148 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and 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 Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. de Jonge MM et al. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. Eur J Cancer. 2017 Feb;72:215-225. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. Rashid MU et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Tonin PN et al. Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999 May;55(5):318-24. Vezina H et al. Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005 Jul;117(2-3):119-32. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jul 01, 2016 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 23, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Dec 07, 2015 | - - |
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:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, no assertion criteria provided | case-control | Bioinformatics dept., Datar Cancer Genetics Limited, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg1443X variant has been previously and extensively reported in the literature. In two selected publications, this variant was identified in 18 of 294 individuals with hereditary breast and ovarian cancer (Selected publications: Tonin 1998, Castilla 1994). This variant was identified as a founder French-Canadian mutation and a common haplotype was described; multiple individuals from these families had breast or ovarian cancers; additional data suggest this variant may also have arisen independently at least three times. The variant is described 83 times in the UMD database as "causal" and 126 times in the BIC database as clinically important. The p.Arg1443X variant leads to a premature stop codon at position 1443, 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 hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. - |
Computational scores
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Pathogenic
D
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Pathogenic
Cadd
Pathogenic
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Benign
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Benign
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Benign
N
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Benign
A;A;A;A;A;A;A;A;A;A;A;N;N;N
Vest4
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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