chr17-43094514-C-CT
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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.1016dupA(p.Val340fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,720 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: 0.0000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0760
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 17-43094514-C-CT is Pathogenic according to our data. Variant chr17-43094514-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 54102.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.1016dupA | p.Val340fs | 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.1016dupA | p.Val340fs | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461720Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727154
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:11
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 06, 2022 | _x000D_ Criteria applied: PVS1, PM2,SUP, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 01, 2019 | The c.1016dupA (p.Val340Glyfs*6) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple families with hereditary breast and ovarian cancer (PMID 7894492, 10441573, 18489799, 28184945) and two individuals with sporadic breast cancer (PMID 23289006). This variant has not been observed in general population databases. Therefore, the c.1016dupA (p.Val340Glyfs*6) variant in the BRCA1 gene is classified as pathogenic. - |
| 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, 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 25, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Apr 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | May 27, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 11, 2022 | PP5, PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2021 | Reported as a pathogenic founder variant in the Norwegian population (Dorum 1999, Rudkin 2006, Torres-Mejia 2014); 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; Reported in individuals and families with Hereditary Breast and Ovarian Cancer (Borg 1999, Foretova 2004, Laraqui 2013, Yablonski-Peretz 2016); 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 known as 1135dupA, 1135insA, and 1128insA; This variant is associated with the following publications: (PMID: 10595257, 15024741, 25371446, 26687385, 16287141, 23199084, 23034506, 32231684, 26350514, 10441573, 23289006, 16509964, 25814778, 18489799, 23697973, 25884701, 26845104, 28993866, 28724667, 27062684, 7894492, 28184945, 26295337, 28637432, 29673794, 28776284, 29339979, 30702160, 30078507, 30322717, 28111427, 31411802) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 04, 2021 | This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast/ovarian cancer in the published literature (PMID: 28724667 (2017), 26350514 (2015), 25186627 (2015), 23289006 (2013), 18489799 (2008), 7894492 (1994)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
| 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 Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Pathogenic, no assertion criteria provided | research | Curoverse | Aug 01, 2015 | Frameshifts in BRCA1 are considered pathogenic, and this is a BRCA1 Val340Gly frameshift variant in exon 10 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Val340Glyfs*6) 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 and/or ovarian cancer (PMID: 10441573, 15024741, 18489799, 23199084, 23289006). This variant is also known as 1135insA. ClinVar contains an entry for this variant (Variation ID: 54102). 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 | Jul 17, 2020 | Variant summary: BRCA1 c.1016dupA (p.Val340GlyfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251174 control chromosomes (gnomAD). c.1016dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Simard_1994, Ramus_2007, Palma_2008, Spearman_2008, Laraqui_2013). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 06, 2021 | This variant inserts 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7894492, 8755943, 10441573, 15024741, 17688236, 18703817, 23289006, 26350514, 27062684, 28724667) and found to segregate with disease in several members of one family (PMID: 17688236). This variant also has been described as a founder mutation in Sweden and Norway (PMID: 8755943, 10441573, 23199084). 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 | Aug 01, 2024 | The c.1016dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1016, causing a translational frameshift with a predicted alternate stop codon (p.V340Gfs*6). This mutation has been detected in multiple breast and/or ovarian cancer families (Foretova L et al. Hum. Mutat., 2004 Apr;23:397-8; Machackova E et al. BMC Cancer, 2008 May;8:140; Laraqui A et al. Int J Med Sci, 2013 Dec;10:60-7; Høberg-Vetti H et al. Eur J Hum Genet, 2016 06;24:881-8; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Meynard G et al. Oncol. Rep., 2017 Mar;37:1573-1578; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Bu H et al. J Obstet Gynaecol Res, 2019 Nov;45:2267-2274; El Ansari FZ et al. BMC Cancer, 2020 Aug;20:747). This mutation has been described as a founder mutation originating from the Eastern population of Norway and Sweden (Dørum A et al. Am. J. Hum. Genet. 1999 Sep;65:671-9; Janaviius R. EPMA J. 2010 Sep;1:397-412; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). Of note, this alteration is also designated as 1135insA and 1128insA 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. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Apr 14, 2010 | - - |
BRCA1-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 31, 2024 | This variant inserts 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7894492, 8755943, 10441573, 15024741, 17688236, 18703817, 23289006, 26350514, 27062684, 28724667) and found to segregate with disease in several members of one family (PMID: 17688236). This variant also has been described as a founder mutation in Sweden and Norway (PMID: 8755943, 10441573, 23199084). 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 neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
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