Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.2488_2504dupAAGTATCCATTGGGACA(p.His835GlnfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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]
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-43093026-A-ATGTCCCAATGGATACTT is Pathogenic according to our data. Variant chr17-43093026-A-ATGTCCCAATGGATACTT is described in ClinVar as Pathogenic. ClinVar VariationId is 280050.Status of the report is reviewed_by_expert_panel, 3 stars.
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Feb 24, 2016
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This duplication of 17 nucleotides in BRCA1 is denoted c.2488_2504dup17 at the cDNA level and p.His835GlnfsX17(H835QfsX17) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 2607_2623dup17. The surrounding sequence is CTTT[dup17]TGAA. The duplication causes a frameshift, which changes a Histidine to a Glutamine at codon 835, and creates a premature stop codon at position 17 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2488_2504dup17 was observed in an individual with serous ovarian cancer and was defined as BRCA1 c.2504_2505het_insAAGTATCCATTGGGACA using alternate nomenclature (George 2013). Based on currently available evidence, we consider this variant to be pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Dec 15, 2017
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. -
The c.2488_2504dup17 variant, located in coding exon 9 of the BRCA1 gene, results from a duplication of AAGTATCCATTGGGACA at nucleotide position 2488, causing a translational frameshift with a predicted alternate stop codon (p.H835Qfs*17). This alteration has been identified in an individual diagnosed with serous ovarian cancer (George J et al. Clin. Cancer Res., 2013 Jul;19:3474-84). Of note, this alteration is also known as c.2504_2505het_insAAGTATCCATTGGGACA 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. -
BRCA1-related disorderPathogenic:1
Feb 14, 2023
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.2488_2504dup17 variant is predicted to result in a frameshift and premature protein termination (p.His835Glnfs*17). This variant was reported in an individual with ovarian cancer (referred to as c.2504_2505het_insAAGTATCCATTGGGACA in George et al. 2013. PubMed ID: 23633455). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/280050/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Jan 06, 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.His835Glnfs*17) 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 ovarian cancer (PMID: 23633455). ClinVar contains an entry for this variant (Variation ID: 280050). For these reasons, this variant has been classified as Pathogenic. -