rs397507239
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5068A>T(p.Lys1690*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,457,970 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: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 4.79
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 17-43067614-T-A is Pathogenic according to our data. Variant chr17-43067614-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 37626.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067614-T-A is described in Lovd as [Pathogenic]. Variant chr17-43067614-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5068A>T | p.Lys1690* | stop_gained | 16/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5068A>T | p.Lys1690* | stop_gained | 16/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457970Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725550
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GnomAD4 genome Cov.: 30
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30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6Other:1
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 | Sharing Clinical Reports Project (SCRP) | May 12, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 29, 2023 | - - |
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, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Dec 16, 2024 | This sequence change creates a premature translational stop signal (p.Lys1690*) 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). Not observed at significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198, 22333603, 26023681, 20104584, 30209399, 29470806, 35698740, 29922827). ClinVar contains an entry for this variant (Variation ID: 37626) classified as pathogenic reviewed by expert panel. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 28, 2017 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
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 | GeneDx | Dec 28, 2022 | 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; 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); Identified in patients with breast, ovarian, pancreatic, or prostate cancer (Robertson et al., 2012; Singh et al., 2018; Mehta et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5187A>T; This variant is associated with the following publications: (PMID: 29446198, 22333603, 26023681, 20104584, 30209399, 29470806, 35698740, 29922827) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2021 | The p.K1690* pathogenic mutation (also known as c.5068A>T), located in coding exon 15 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5068. This changes the amino acid from a lysine to a stop codon within coding exon 15. 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). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620) and has been reported in the literature in a patient diagnosed with triple negative breast cancer (Robertson L. Br J Cancer. 2012 Mar;106(6):1234-8). 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 | curation | Sema4, Sema4 | Dec 29, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2022 | For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 37626). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22333603, 29446198, 29470806). This variant is present in population databases (rs397507239, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys1690*) 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). - |
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
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at