Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3967del(p.Gln1323LysfsTer2) 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 17-43091563-TG-T is Pathogenic according to our data. Variant chr17-43091563-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 55063.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091563-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43091563-TG-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Oct 18, 2016
Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 03, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Aug 16, 2018
This deletion of one nucleotide in BRCA1 is denoted c.3967delC at the cDNA level and p.Gln1323LysfsX2 (Q1323KfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAA[delC]AAAT. The deletion causes a frameshift which changes a Glutamine to a Lysine at codon 1323, and creates a premature stop codon at position 2 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. Also reported as BRCA1 c.4086delC using alternate nomenclature, this variant has been observed in at least one individual with a family history of breast and ovarian cancer (Meyer 2003). We consider this variant to be pathogenic. -
The c.3967delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3967, causing a translational frameshift with a predicted alternate stop codon (p.Q1323Kfs*2). This alteration was reported in one German breast and ovarian cancer family (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Aug 29, 2023
This sequence change creates a premature translational stop signal (p.Gln1323Lysfs*2) 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 BRCA1-related conditions (PMID: 12938098, 28888541). ClinVar contains an entry for this variant (Variation ID: 55063). For these reasons, this variant has been classified as Pathogenic. -