Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3296delC(p.Pro1099LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 17-43092234-AG-A is Pathogenic according to our data. Variant chr17-43092234-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 54824.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092234-AG-A is described in Lovd as [Pathogenic]. Variant chr17-43092234-AG-A is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and 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 detected in at least 7 individuals affected with breast and ovarian cancer (PMID: 10498392, 19499246, 22798144, 29020732, 29673794, 30207098, 33850850) and reported in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000654). 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. -
Jan 19, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3296delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3296, causing a translational frameshift with a predicted alternate stop codon (p.P1099Lfs*10). This alteration has been reported in individuals with familial breast and/or ovarian cancer in multiple populations (Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Koczkowska M et al. Cancers (Basel), 2018 Nov;10; Lim MC et al. J Cancer Res Clin Oncol, 2009 Nov;135:1593-9; Seong MW et al. Clin Genet, 2009 Aug;76:152-60; Southey MC et al. Br. J. Cancer, 1999 Jan;79:34-9; Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68; Cao WM et al. BMC Cancer, 2016 Feb;16:64; Li A et al. Gynecol Oncol, 2018 10;151:145-152). Of note, this alteration is also designated as 3415delC in published literature. In addition to the information 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Apr 26, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54824). This variant is also known as 3415delC. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1099Leufs*10) 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). -
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto