ABRAXAS1

Gene Facts

• HGNC Symbol: ABRAXAS1 (HGNC:25829)
• HGNC Name: abraxas 1, BRCA1 A complex subunit
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CCDC98, FAM175A
• Alias symbols: FLJ13614, ABRA1, ABRAXAS
• %HI: 64
• pLI: 0
• LOEUF: 1.35
• Cytoband: 4q21.23
• Genomic Coordinates:

  GRCh37/hg19:	chr4:84380670-84406253
  GRCh38/hg38:	chr4:83459517-83485100

• MANE Select Transcript: NM_139076.3 ENST00000321945.12
• Function: Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically re... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-30497
• ClinGen Curation ID: CCID:006604
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 07/18/2023

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Evidence

• PUBMED: 31159747
  Tsaousis et al BMC Cancer . 2019, used NGS w/ a multigene panel to study cancer predisposition genes among families to determine genetic cause of cancer heritability. Their aim was to investigate the extent of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in their laboratory. They studied 1197 individuals. In ABRAXAS1, they identified a frameshift in the last exon (exon 9) which they called pathogenic (Supp Table 2) NM_139076.2(ABRAXAS1):c.1106dupG (p.Ser370Ilefs*2). However, this variant is not anticipated to result in nonsense mediated decay, disrupts the last 40 amino acids of the ABRAXAS1 protein. It has conflicting interpretations in ClinVar of Uncertain and the 1 Path entry by this paper; variant ID: 128215). Of note, this variant also overlaps a repeat block (homology from pseudogene – authors do say they confirmed via Sanger). Authors do not comment on segregation of the variant (de novo, inherited, etc)
• PUBMED: 37198153
  Sachsenweger et al 2023 in journal Cell Death and Disease identified two heterozygous truncating germline variants in ABRAXAS1 among early-onset breast cancer patients. One of the two truncating variants has been described prior in study PMID: 31159747 (different patient in the current study). The other variant is a stop gain in exon 6 of this gene (Exon 6 | c.577C>T | p.Arg193*) with conflicting interpretation of uncertain and likely pathogenic in ClinVar (variation ID: 496539). The protein product for this gene, of note, partners with BRCA1. The truncating variants were examined in patient-derived lymphoblastoid cells and in genetically manipulated mammary epithelial cells. By use of these strategies, authors demonstrated that these truncating ABRAXAS1 variants exerted dominant effects on BRCA1 functions. Their experiment suggest compromised BRCA1-A complex formation in ABRAXAS1 c.1106dup-mutated cells, and to some extent also in ABRAXAS1 c.577C>T-mutated cells.
• PUBMED: 29484706
  PMID: 29484706: Anna-Guacci et al in J Clin Lab Analysis 2018, found several variants with conflicting interpretation of pathogenicity, among which was a small in frame deletion (p.Lys368del) in FAM175A observed in 11 of 34 cases with family history of an inherited cancer. It is classified as uncertain in ClinVar (variation ID: 241853). No comment on segregation of variant is provided by authors.

• HI Evidence Comments: Currently, there is limited evidence for haploinsufficiency. This gene has been described in somatic disease, lung cancer, head and neck cancer. For germline variants in cancer predisposition syndromes, its involvement in the genetic landscape of hereditary cancer is sparse and currently there is a lack of loss of function variants described. Potential LOF variants have been reported for FAM175A in large familial cancer studies (Bertelsen 2019 (PMID: 31263571), Siraj 2017 (PMID: 28975465), Pritchard 2016 (PMID: 27433846), disease association is currently unknown. Recent evidence from PMID: 37198153 also suggests that ABRAXAS1 may interact with a BRCA1 complex to aid in DNA double strand repair.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: No evidence for triplosensitivity