17-43094169-ACT-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1360_1361del(p.Ser454Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S454S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.238
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 17-43094169-ACT-A is Pathogenic according to our data. Variant chr17-43094169-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 37406.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094169-ACT-A is described in Lovd as [Pathogenic]. Variant chr17-43094169-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.1360_1361del | p.Ser454Ter | frameshift_variant | 10/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.1360_1361del | p.Ser454Ter | frameshift_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251004Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135664
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461764Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727182
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
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, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Ser454X variant was identified in at least 5 of 112950 proband chromosomes (frequency: 0.00004) from individuals or families with hereditary breast or ovarian cancer (Judkins 2005, Ottini 2000, Risch 2001, van Orsouw 1999). The variant was also previously identified by our laboratory in 1 individual with breast and ovarian cancer. The variant was identified in dbSNP (ID: rs80357969) “With Pathogenic allele”, and the BIC database (19X as Pathogenic). The p.Ser454X variant leads to a premature stop codon at position 454, 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. - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| 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 | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jan 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2018 | The c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 10528853, 11056688, 17148771), and has been reported 19 times in Breast Cancer Information Core. This variant is observed at a low minor allele frequency (2/245828) in gnomAD. Therefore, the c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is classified as pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 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; Reported in association with breast and ovarian cancer (Ottini 2000, Zhang 2011); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also know as c.1479_1480delAG; 1479delAG; This variant is associated with the following publications: (PMID: 31447099, 10528853, 21324516, 11179017, 28087643, 11056688, 22874498, 26681312, 17148771, 27062684, 29339979, 30720243) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 25, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individual and families with breast and ovarian cancer in the published literature (PMID: 31209999 (2019), 26219728 (2016), 11056688 (2000)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 08, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 03, 2014 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Ser454*) 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 (rs80357969, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10528853, 22874498, 26219728, 26681312). This variant is also known as 1479delAG. ClinVar contains an entry for this variant (Variation ID: 37406). 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 | Dec 09, 2016 | Variant summary: The BRCA1 c.1360_1361delAG (p.Ser454Terfs) 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. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121340 (1/60670), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest was reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest 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 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2022 | The c.1360_1361delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 1360 to 1361, causing a translational frameshift with a predicted alternate stop codon (p.S454*). This alteration has been reported in several unrelated individuals diagnosed with breast and/or ovarian cancer (van Orsouw NJ et al. J. Med. Genet. 1999 Oct;36(10):747-53; Ottini L et al. Breast Cancer Res. 2000 Mar;2(4):307-10; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec 6;98(23):1694-706; Ozcelik H et al. J. Mol. Diagn. 2012 Sep;14(5):467-75; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 1479delAG 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This variant deletes 2 nucleotides 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 is also known as 1479delAG based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in over twenty individuals affected with breast and/or ovarian cancer, and in high-risk breast and ovarian cancer families (PMID: 10528853, 11056688, 11938448, 17148771, 21324516, 22874498, 26219728, 26681312, 27208206, 32245699, 32438681, 33403015, 33471991). This variant has been identified in 29 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 2/251004 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. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 12, 2023 | - - |
Computational scores
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