Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2488_2504dupAAGTATCCATTGGGACA(p.His835fs) variant causes a frameshift 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 (★★★). 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 17-43093026-A-ATGTCCCAATGGATACTT is Pathogenic according to our data. Variant chr17-43093026-A-ATGTCCCAATGGATACTT is described in ClinVar as [Pathogenic]. Clinvar id is 280050.Status of the report is reviewed_by_expert_panel, 3 stars.
Quest Diagnostics Nichols Institute San Juan Capistrano
May 19, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Feb 24, 2016
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, 1 Pathogenic:1
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Dec 15, 2017
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 disorder Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Feb 14, 2023
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 syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Aug 18, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280050). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 23633455). This variant is not present in population databases (gnomAD no frequency). 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). -