chr17-43093193-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2338C>T(p.Gln780Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,613,642 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. Q780Q) 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.2338C>T | p.Gln780Ter | stop_gained | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2338C>T | p.Gln780Ter | stop_gained | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250740Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135506
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461616Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2AN XY: 727086
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74254
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:14
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 10, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Jul 21, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PS4 - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 17, 2022 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 27, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 15, 2012 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Jun 11, 2024 | - - |
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 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 personal and family history of BRCA1-associated cancers (Friedman 1995, Peelen 1997, Frank 1998, Walsh 2011, Weren 2016, Rashid 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 2457C>T; This variant is associated with the following publications: (PMID: 22970155, 9150151, 27767231, 27153395, 22752604, 8533757, 11773283, 9667259, 16615107, 16234499, 11748305, 21324516, 11597388, 25525159, 23199084, 15515971, 16267036, 14574155, 18563556, 25722380, 22006311, 7663517, 29470806, 29446198, 30720243, 30322717, 31528241, 31825140, 32719484, 33726785) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 20, 2022 | - - |
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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 30, 2021 | The BRCA1 c.2338C>T, p.Gln780Ter variant (rs80356945), has been reported in multiple individuals with breast or ovarian cancer (Hogervorst 1995, Walsh 2011). The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 54540) and is found in 1 out of 250740 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Hogervorst F et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nat Genet. 1995; 10(2):208-12. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011; 108(44):18032-7. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 22, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has reported in individuals affected with breast and/or ovarian cancer in the published literature (PMIDs: 9667259 (1998), 11802209 (2002), 16683254 (2006), 21324516 (2011), 22752604 (2012), 29470806 (2018), 30322717 (2018)), as well as in an individual affected with fallopian tube carcinoma (PMID: 22006311 (2011)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Gln780*) 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 (rs80356945, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7663517, 9667259, 16683254, 21324516, 22006311, 22752604). This variant is also known as 2457C>T, Q780X. ClinVar contains an entry for this variant (Variation ID: 54540). 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 | Oct 01, 2021 | Variant summary: BRCA1 c.2338C>T (p.Gln780X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 250740 control chromosomes. p.Gln780X has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Friedman_1995, Meindl_2002, Judkins_2005, Juwle_2012, Pennington_2014). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 22, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 28, 2016 | The p.Gln780X variant in BRCA1 has been reported in >30 individuals with BRCA1-a ssociated cancers (Hogervorst 1995, Frank 1998, Meindl 2002, van der Hout 2006, Walsh 2011, Zhang 2011, Juwle 2012, Breast Cancer Information Core (BIC) databas e). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 780, which is predicted to l ead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogeni c on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV0002 82277.1). In summary, this variant meets our criteria to be classified as pathog enic for HBOC in an autosomal dominant manner. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 17, 2022 | The p.Q780* pathogenic mutation (also known as c.2338C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2338. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported numerous times in breast and ovarian cancer cohorts of varying ethnicities (Janaviius R. EPMA J. 2010 Sep;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Juwle A and Saranath D Med. Oncol. 2012 Dec;29:3272-81; Singh J et al Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). 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 | curation | Sema4, Sema4 | Apr 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 21, 2022 | 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 individuals affected with ovarian and breast cancer (PMID: 21324516, 22006311, 22752604, 24240112, 29470806, 30322717, 31076742, 33726785, 9667259, Color internal data). In a large breast cancer case-control study conducted by the Breast Cancer Association Consortium, this variant was reported in 4/60466 cases, 0/53461 controls; p-value=0.128; (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001125). This variant has been identified in 1/250740 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 05, 2022 | - - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Gln780X variant was identified in 7 of 3350 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancers and was not identified in 100 control chromosomes from healthy individuals (Frank 1998, Hogervorst 1995, Juwle 2012, Zhang 2011). A study looking at MYC oncogene activation in BRCA1 germline vs sporadic breast tumours, found MYC was preferentially amplified in BRCA1 promoter methylated tumours and tumours carrying BRCA1 germline mutations, including the Gln780X, supporting MYC activated progression of BRCA1-associated breast cancers (Grushko 2004). In a Dutch study looking at the distribution of (pre)malignant lesions in both breast and adnexal (ovary and Fallopian tube) tissues of hereditary breast/ovarian high risk patients, compared to controls, the Gln780X mutation was associated with lesions in both the ovaries and Fallopian tubes (Hermsen 2006). The variant was also identified in dbSNP (ID: rs80356945) “With pathogenic/uncertain significance allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Gln780X was also identified in HGMD, ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) derived from Myriad reports; classified as pathogenic by BIC; classified as pathogenic by Counsyl; and unclassified by Invitae), the BIC database (36X with pathogenic clinical importance), GeneInsight VariantWire database (classified as benign by a clinical laboratory)and UMD (1X as a 5-Causal variant). The variant was not identified in any cohorts from the general population, including the 1000 Genome Project, HapMap projects, NHLBI Exome Sequencing Project (Exome Variant Server), or the Exome Aggregation Consortium (ExAC) database; COSMIC, LOVD, Breast Cancer IARC or LOVD-IARC. The p.Gln780X variant leads to a premature stop codon at position 780, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at