rs80357347
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5179A>T(p.Lys1727Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,840 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. K1727K) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5179A>T | p.Lys1727Ter | stop_gained | 18/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5179A>T | p.Lys1727Ter | stop_gained | 18/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1458840Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726040
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
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 | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
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 | All of Us Research Program, National Institutes of Health | Jan 06, 2024 | The c.5179A>T (p.Lys1727*) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast cancer, ovarian cancer and uterine cancer (PMID: 7493024, 10699917, 11802209, 16287141). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.5179A>T (p.Lys1727*) variant of the BRCA1 gene is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 10, 2012 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 03, 2016 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 07, 2020 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 27, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, the variant has been reported in multiple individuals and families with hereditary breast and/or ovarian cancer (PMID: 29446198 (2018), 16287141 (2005), 11802209 (2002), 10699917 (2000), 7493024 (1995)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in association with BRCA1-related cancers (Gayther et al., 1995; Spitzer et al., 2000; Kroiss et al., 2005; Hahnen et al., 2017; Evans et al., 2022); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5298A>T; This variant is associated with the following publications: (PMID: 11802209, 29446198, 27756336, 10699917, 7493024, 16287141, 28715532, 27150160, 30787465, 30209399, 33758026) - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Lys1727*) 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 hereditary breast cancer (PMID: 7493024, 16287141). It has also been observed to segregate with disease in related individuals. This variant is also known as 5298A>T. ClinVar contains an entry for this variant (Variation ID: 37645). For these reasons, this variant 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2019 | The p.Lys1727X variant in BRCA1 has been reported in at least 10 individuals with hereditary breast and/or ovarian cancer (HBOC) and segregated with disease in 1 affected relative (Gayther 1995, Kroiss 2005, Rebbeck 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1727, which is predicted to lead to a truncated or absent protein. Loss-of-function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In vitro functional studies support an impact on protein function (Findlay 2018). In addition, this variant was classified as Pathogenic by the ClinGen-approved ENIGMA expert panel (Variation ID: 37645). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2021 | The p.K1727* pathogenic mutation (also known as c.5179A>T), located in coding exon 17 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5179. This changes the amino acid from a lysine to a stop codon within coding exon 17. This pathogenic mutation has been reported in multiple individuals or families with ovarian and/or breast cancer, as well as in one individual diagnosed with uterine cancer (Gayther SA et al. Nat. Genet., 1995 Dec;11:428-33; Spitzer E et al. Int. J. Cancer, 2000 Feb;85:474-81; Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Kroiss R et al. Hum Mutat, 2005 Dec;26:583-9; Walker LC et al. Eur J Hum Genet, 2017 04;25:432-438; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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). Of note, this alteration is also designated as 5298A>T 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at