17-61683605-AT-ATT
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_032043.3(BRIP1):c.3440dupA(p.Asn1147LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,611,944 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: 0.000050 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 frameshift
NM_032043.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.808
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0827 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152066Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000801 AC: 20AN: 249660Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135134
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GnomAD4 exome AF: 0.0000500 AC: 73AN: 1459760Hom.: 0 Cov.: 32 AF XY: 0.0000592 AC XY: 43AN XY: 726276
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74412
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2024 | The c.3440dupA variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of A at nucleotide position 3440, causing a translational frameshift with a predicted alternate stop codon. This alteration occurs at the 3' terminus of BRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 102 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was detected in an 8-year-old patient with acute lymphoblastic leukemia (ALL) (Douglas SPM et al. Sci Rep, 2022 Jun;12:10670). Structural and functional analysis suggest that at least two residues contained in the impacted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal, 2010 Jan;3:ra3; Xie J et al. PLoS Genet., 2012 Jul;8:e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2018 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2024 | This sequence change creates a premature translational stop signal (p.Asn1147Lysfs*2) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs753683450, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with clinical features of BRIP1-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 483163). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 26, 2019 | Frameshift variant predicted to result in protein truncation as the last 103 amino acids are lost and replaced with one incorrect amino acid, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29922827, 20159562, 21127055, 20068231, 22792074) - |
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