Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.922_924delAGCinsT(p.Ser308fs) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S308S) has been classified as Likely benign. 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 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 17-43094607-GCT-A is Pathogenic according to our data. Variant chr17-43094607-GCT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55753.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
Sep 16, 2011
Sharing Clinical Reports Project (SCRP)
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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not providedPathogenic:2
Sep 11, 2018
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Also known as 1041_1043delAGCinsT; This variant is associated with the following publications: (PMID: 32164585, 28205045, 19499246, 15365993, 22006311, 26402875, 27383479, 22798144, 22382806, 16455195, 22217648, 29673794, 28977883, 29770616, 28111427, 30309222) -
Feb 08, 2017
Quest Diagnostics Nichols Institute San Juan Capistrano
This variant is located in the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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. -
Apr 30, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.922_924delAGCinsT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide introducing a stop codon (p.S308*). This alteration has been reported multiple times in Korean individuals from high risk breast and ovarian cancer cohorts (Seo JH et al. Hum. Mutat. 2004 Oct;24:350; Ahn SH et al. Cancer Lett, 2007 Jan;245:90-5; Lim MC et al. J. Cancer Res. Clin. Oncol. 2009 Nov;135:1593-9; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Choi MC et al. Int. J. Gynecol. Cancer, 2015 Oct;25:1386-91; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Choi MC et al. J Gynecol Oncol, 2018 Jul;29:e43; Choi MC et al. Int J Gynecol Cancer, 2018 02;28:308-315; Kim SI et al. Cancer Res Treat, 2020 Oct;52:1229-1241). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group SPathogenic:1
Jun 15, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:1
Jan 14, 2025
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.Ser308*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer and is a recurrent variant in the Korean population (PMID: 15365993, 16455195, 22006311, 22798144, 26402875). This variant is also known as 1041_1043delAGCinsT. For these reasons, this variant has been classified as Pathogenic. -