Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1601_1602delAG(p.Gln534fs) 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 17-43093928-CCT-C is Pathogenic according to our data. Variant chr17-43093928-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 240774.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093928-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43093928-CCT-C is described in Lovd as [Pathogenic].
This variant deletes 2 nucleotides 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. This variant has been reported in an individual affected with breast cancer (PMID: 25452441). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 13, 2018
The c.1601_1602delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 1601 to 1602, causing a translational frameshift with a predicted alternate stop codon (p.Q534Rfs*3). This alteration was detected in 1 individual in a cohort of 1824 patients with triple negative breast cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jul 27, 2015
This deletion of 2 nucleotides in BRCA1 is denoted c.1601_1602delAG at the cDNA level and p.Gln534ArgfsX3 (Q534RfsX3) at the protein level. This deletion is also known as BRCA1 1720delAG using alternate nomenclature. The normal sequence, with the bases that are deleted in braces, is AATC[AG]GGAA. The deletion causes a frameshift, which changes a Glutamine to an Arginine at codon 534, and creates a premature stop codon at position 3 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.1601_1602delAG has been reported in at least one individual with triple negative breast cancer (Couch 2015). we consider this variant to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
May 26, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 240774). This premature translational stop signal has been observed in individual(s) with triple-negative breast cancer (PMID: 25452441). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln534Argfs*3) 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). -