rs80356903
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3718C>T(p.Gln1240Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,864 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: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 stop_gained
NM_007294.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 2.84
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]
Genome browser will be placed here
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 17-43091813-G-A is Pathogenic according to our data. Variant chr17-43091813-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54978.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091813-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091813-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3718C>T | p.Gln1240Ter | stop_gained | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3718C>T | p.Gln1240Ter | stop_gained | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727228
GnomAD4 exome
AF:
AC:
2
AN:
1461864
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12
| 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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This variant BRCA1 c.3718C>T (also known as BRCA1 3837C>T in the literature) creates a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in individuals affected with endometrial, breast and ovarian cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). 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. Based on available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jan 22, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 10, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM2_supporting; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2022 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 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 and family history of breast and/or ovarian cancer (Balleine et al., 2010; Novakovic et al., 2012; Wang et al., 2015); 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 3837C>T; This variant is associated with the following publications: (PMID: 25525159, 25480878, 24333842, 17645508, 22923021, 17761984, 27393621, 20815029, 23397983, 26833046, 18446624, 28740454, 28888541, 28724667, 29446198, 30702160, 31825140, 32918181) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2023 | his variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with pancreatic cancer (PMID: 32918181 (2021)), ovarian cancer (PMID: 28740454 (2017)), and breast cancer (PMID: 31957001 (2020), 30702160 (2019), 28724667 (2017), 27393621 (2016), 25480878 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
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 | Jul 29, 2015 | The p.Gln1240X variant in BRCA1 has been reported in 2 individuals with endometr ial cancer (Kwon 2008, Conner 2014) and at least 7 individuals with breast and/o r ovarian cancer (Novakovic 2012, Wang 2015, Breast Cancer Information Core (BIC )). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1240, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA1 function is an establish ed disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) base d upon the predicted impact to the protein, presence in affected individuals, an d absence in controls. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 23, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1240*) 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 premature translational stop signal has been observed in individual(s) with breast, ovarian, and endometrial cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54978). This variant is also known as 3837C>T. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 10, 2023 | This variant BRCA1 c.3718C>T (also known as BRCA1 3837C>T in the literature) creates 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 individuals affected with endometrial, breast and ovarian cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). 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. Based on available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2022 | The p.Q1240* pathogenic mutation (also known as c.3718C>T) located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3718. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in many individuals with personal and family histories of breast, ovarian, fallopian tube, and prostate cancer (Callahan MJ et al. J. Clin. Oncol. 2007 Sep;25:3985-90; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Connor JR et al. Gynecol. Oncol. 2014 Feb;132:280-6; Wang C et al. Ann. Oncol. 2015 Mar;26:523-8; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158:455-62; Cvelbar M et al. Radiol. Oncol. 2017 Jun;51(2):187-194). It has also been reported in a female patient diagnosed with advanced metastatic endometrial cancer who had a family history of melanoma, breast cancer, and prostate cancer (Kwon JS et al. Int. J. Gynecol. Cancer. 2008 May-Jun;18:546-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 3837C>T and Q1240X 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at