Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3640G>T(p.Glu1214*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 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.
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]
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 17-43091891-C-A is Pathogenic according to our data. Variant chr17-43091891-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 54949.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091891-C-A is described in Lovd as [Pathogenic]. Variant chr17-43091891-C-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
Dec 05, 2014
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only
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Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
Variant allele predicted to encode a truncated non-functional protein. -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 12, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This rare nonsense variant c.3640G>T (p.Glu1214*) in the BRCA1 gene is absent in public databases and is predicted to result in a loss of function of BRCA1. This variant has been observed in at least 10 unrelated individuals with breast cancer (PMID 8723683, 9197534, 9150151, 24884479, 24719479). Therefore, this c.3640G>T (p.Glu1214*) variant in the BRCA1 gene is classified as pathogenic. -
Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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May 27, 2024
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PVS1; PM2_supporting; PM5_PTC_Strong -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jul 02, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.3640G>T (p.Glu1214X) 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. The variant was absent in 246036 control chromosomes. c.3640G>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. -
Apr 05, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Glu1214X variant in BRCA1 has been reported in at least 4 individuals with BRCA1-associated cancers (Peelen 1997, Ishikawa 2014, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1214, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in HBOC. Furthermore, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299984.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Supporting -
Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Glu1214*) 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 a personal and/or extensive family history of breast and/or ovarian cancer (PMID: 9150151, 16683254, 20104584, 24719479, 26848529). ClinVar contains an entry for this variant (Variation ID: 54949). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Mar 23, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 8 individuals affected with breast, ovarian and fallopian tube cancer (PMID: 8723683, 9197534, 24719479, 24884479, 24249303, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA1_001445) and two individuals affected with prostate cancer (PMID: 31214711). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Oct 14, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.E1214* pathogenic mutation (also known as c.3640G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3640. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple Japanese patients and families with breast and ovarian cancer (Katagiri T et al. Hum. Mutat. 1996;7:334-9; Takano M et al. Jpn. J. Cancer Res. 1997 Apr;88:407-13; Ishikawa H et al. Jpn. J. Clin. Oncol. 2014 Jun;44:597-601). Additionally, 1/103 women in a high-grade serous ovarian cancer cohort was found to have this mutation (Schrader KA et al. Obstet Gynecol 2012 Aug;120:235-40). This alteration was also identified in a Brazilian patient with early onset breast cancer (Silva FC et al. BMC Med. Genet. 2014 May;15:55) and a Dutch or Belgian HBOC family (Peelen T et al. Am. J. Hum. Genet. 1997 May;60:1041-9). Of note, this alteration is also designated as 3759G>T, E1214X, and 1214 GAG>TAG 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. -
Breast and/or ovarian cancer Pathogenic:1
Jun 11, 2019
CZECANCA consortium
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
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Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PM2_Supporting+PVS1+PS4_Moderate -
Breast neoplasm Pathogenic:1
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A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center
Significance: Pathogenic
Review Status: criteria provided, single submitter