rs587780262
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_139076.3(ABRAXAS1):c.1106dupG(p.Ser370IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
ABRAXAS1
NM_139076.3 frameshift
NM_139076.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.419
Genes affected
ABRAXAS1 (HGNC:25829): (abraxas 1, BRCA1 A complex subunit) This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-83462592-T-TC is Pathogenic according to our data. Variant chr4-83462592-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128215.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251388Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135868
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727214
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GnomAD4 genome 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74378
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single nucleotide duplication in exon 9 of the FAM175A (ABRAXAS1) mRNA (c.1106dupG). This results in a frameshift after codon 370 and the creation of a premature translation stop signal 2 amino acid residues later. This mutation is expected to result in loss of normal protein function through protein truncation, where the phospho-SXXF motif, necessary for interaction with BRCA1 (PMID: 17525340) is lost. This mutation has been reported in 2 ovarian cancer patients (PMID: 24240112 ). The mutation database ClinVar contains entries for this variant (Variation ID: 128215). - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2020 | The c.1106dupG variant, located in coding exon 9 of the FAM175A gene, results from a duplication of G at nucleotide position 1106, causing a translational frameshift with a predicted alternate stop codon (p.S370Ifs*2). This alteration has been reported in individuals diagnosed with diffuse glioma and ovarian cancers (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11, Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration is expected to result in loss of function by premature protein truncation as it removes a region of the protein involved in binding of BRCA1 (Liu Z et al. Nat. Struct. Mol. Biol., 2007 Aug;14:716-20, Wang B et al. Science, 2007 May;316:1194-8). However, loss of function of FAM175A has not been clearly established as a mechanism of disease. Based on data from the Genome Aggregation Database (gnomAD), the c.1106dupG allele has a overall frequency of approximately 0.009194% (26/282792). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 18, 2023 | This sequence change creates a premature translational stop signal (p.Ser370Ilefs*2) in the ABRAXAS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the ABRAXAS1 protein. This variant is present in population databases (rs587780262, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with diffuse glioma, individuals undergoing testing for a personal or family history of breast and/or ovarian cancer, and/or Kaposi sarcoma (PMID: 24240112, 26556299, 31159747, 31361614, 31980526). This variant is also known as FAM175 c.1106dup. ClinVar contains an entry for this variant (Variation ID: 128215). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at