rs80357233
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2138C>G(p.Ser713Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,104 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. S713S) has been classified as Likely benign. 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.2138C>G | p.Ser713Ter | stop_gained | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2138C>G | p.Ser713Ter | stop_gained | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135766
GnomAD4 exome Cov.: 41
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 27, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 11139249, 21913181, 22762150, 26845104, 28724667, 30702160, 31825140), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001833). This variant has been identified in 2/282518 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. - |
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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Apr 21, 2016 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 18, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. It has been reported in families affected with breast/ovarian cancer in the published literature (PMID: 11139249 (2001), 29446198 (2018), 30702160 (2019)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA1 related cancers. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Vaziri 2001, Finkleman 2012, Litton 2012, Monk 2015, Donenberg 2016, Wang 2019); Not observed at a 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 2257C>G; This variant is associated with the following publications: (PMID: 25400221, 25525159, 15829246, 26848529, 25722380, 21913181, 22430266, 11139249, 27150160, 27469594, 30702160, 30720243, 30968603, 29625052, 26689913, 32719484, 32341426, 31825140, 29339979, 30078507, 29446198, 28176296, 28724667) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 27, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Ser713*) 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 (rs80357233, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 11139249, 21913181, 22430266). This variant is also known as 2257C>G. ClinVar contains an entry for this variant (Variation ID: 37451). 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 | Feb 16, 2017 | Variant summary: The BRCA1 c.2138C>G (p.Ser713X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2157dupA. p.Glu720fsX6; c.2197_2201delGAGAA, p.Glu733fsX5; c.2241delC, p.Asp749fsX4). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/122388 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in numerous affected individuals in the literature. Functional studies have demonstrated a reduction on multiple aspects of BRCA1 function attributed to this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2022 | The p.S713* pathogenic mutation (also known as c.2138C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2138. This changes the amino acid from a serine to a stop codon within coding exon 9. This mutation was previously identified in individuals and families with breast and/or ovarian cancer diagnoses (Vaziri SA et al. Hum. Mutat. 2001;17:74; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Shi T et al. Int. J. Cancer 2017 05;140:2051-2059; Bhaskaran SP et al. Int. J. Cancer 2019 Jan). 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). Of note, this alteration is also designated as 2257C>G 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 | Mar 16, 2023 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 11139249, 21913181, 22762150, 26845104, 28724667, 30702160, 31825140), and has been identified in 8 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001833). This variant has been identified in 2/282518 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. - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 03, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at