rs80357989
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.850_851insTCATTAC(p.Gln284LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 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: 6.8e-7 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.50
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 17-43094680-T-TGTAATGA is Pathogenic according to our data. Variant chr17-43094680-T-TGTAATGA is described in ClinVar as [Pathogenic]. Clinvar id is 55735.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.850_851insTCATTAC | p.Gln284LeufsTer5 | frameshift_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.850_851insTCATTAC | p.Gln284LeufsTer5 | frameshift_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461682Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727108
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Nov 17, 1998 | - - |
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) | Oct 18, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS4_STR, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
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 | Aug 04, 2016 | The p.Gln284fs variant in BRCA1 has been reported in >10 Caucasian individuals with BRCA1-associated cancers (Ozcelik 2003, Stegel 2011, Krajc 2014) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 284 and leads to a premature stop codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2022 | This sequence change creates a premature translational stop signal (p.Gln284Leufs*5) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55735). This premature translational stop signal has been observed in individual(s) with pancreatic ductal adenocarcinoma and a personal and/or family history of breast and/or ovarian cancer (PMID: 12920083, 16287141, 22923021, 23635950, 25940717, 26306726, 28740454). This variant is not present in population databases (gnomAD no frequency). - |
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2017 | This duplication of seven nucleotides in BRCA1 is denoted c.844_850dupTCATTAC at the cDNA level and p.Gln284LeufsX5 (Q284LfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CAGC[dupTCATTAC]AGCA. The duplication causes a frameshift which changes a Glutamine to a Leucine at codon 284, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.844_850dupTCATTAC, previously published as 969ins7 using alternate nomenclature, has been reported in multiple individuals with hereditary breast and/or ovarian cancer and is described as a recurrent variant in the Slovenian population (Stegel 2011, Navokovic 2012, Dobricic 2013, Karami 2013, Cini 2016, Cvelbar 2017). We consider this variant to be pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 02, 2020 | This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast, ovarian, and pancreatic cancers in the published literature (PMID: 30940100 (2019), 26306726 (2015), 25940717 (2015), 23635950 (2013), 12920083 (2003)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2020 | The c.844_850dupTCATTAC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TCATTAC at nucleotide position 844, causing a translational frameshift with a predicted alternate stop codon (p.Q284Lfs*5). This mutation has been reported in several high-risk breast/ovarian cancer families (Ozcelik H, J. Med. Genet. 2003 Aug; 40(8):e91; Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Dobrii J et al. J Hum Genet, 2013 Aug;58:501-7; Krajc M et al. Clin Genet, 2014 Jan;85:59-63; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Cini G et al. BMC Med Genet, 2016 Feb;17:11; Cvelbar M et al. Radiol Oncol, 2017 Jun;51:187-194; Gornjec A et al. BMC Cancer, 2019 Apr;19:296; Nguyen-Dumont T et al. Genet Res (Camb), 2020 08;102:e6) as well as in a pancreatic cancer cohort (Holter S et al. J Clin Oncol, 2015 Oct;33:3124-9). In particular, this mutation has been reported frequently in the Slovenian population (Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Krajc M et al. Clin Genet, 2014 Jan;85:59-63). Of note, this alteration is also referred to as 969ins7, 970ins7 , and 850_851insTCATTAC in the 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 | Jun 30, 2023 | This variant inserts 7 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 969ins7 and 970ins7 in the literature. 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 detected in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 12920083, 23635950, 26852130) including recurrent affected families in Slovenia (PMID: 22923021). 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. - |
Rhabdomyosarcoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 10, 2015 | - - |
Computational scores
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Calibrated prediction
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at