rs778664039
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_032043.3(BRIP1):βc.3390_3393delβ(p.Tyr1131LeufsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000149 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. I1130I) has been classified as Likely benign.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000016 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 frameshift
NM_032043.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.24
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 Pathogenic. Variant got 12 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. There are 4 pathogenic variants in the truncated region.
PP5
?
Variant 17-61683652-AATAG-A is Pathogenic according to our data. Variant chr17-61683652-AATAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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BRIP1 | NM_032043.3 | c.3390_3393del | p.Tyr1131LeufsTer18 | frameshift_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3390_3393del | p.Tyr1131LeufsTer18 | frameshift_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250266Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135470
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1460812Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 726744
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74480
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2023 | The c.3390_3393delCTAT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides at positions 3390 to 3393, causing a translational frameshift with a predicted alternate stop codon (p.Y1131Lfs*18). This alteration occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 101 amino acids of the protein. However, premature stop codons are typically deleterious in nature; however, functional and structural analyses suggest that at least two residues contained in this deleted region (Thr1133 and Lys1249) have functional importance (Leung CC et al. J Biol Chem. 2011 Feb 11;286(6):4292-301; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 17, 2024 | This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with the last 119 amino acids of the protein replaced with 17 novel amino acids. The truncation is expected to disrupt the TopBP1 binding region and an acetylation site in the C-terminus of the BRIP1 protein, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals with early-onset breast cancer (Color internal data) and in an individual affected with prostate cancer (PMID: 27701467). This variant has been identified in 9/250266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the exact mechanism by which this variant causes disease is yet to be determined, the available evidence indicates that this variant is likely to disrupt normal BRIP1 protein function. Therefore, this variant is classified as Likely Pathogenic. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Tyr1131Leufs*18) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 119 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs778664039, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 27701467). This variant is also known as p.I1130fs. ClinVar contains an entry for this variant (Variation ID: 229712). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
BRIP1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 24, 2024 | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2023 | Variant summary: BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsX18), located in the last exon, results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been observed in individuals with breast and/or ovarian cancer and early-onset Prostate cancer as reported in the HGMD database. The variant allele was found at a frequency of 3.6e-05 in 250266 control chromosomes. To our knowledge, c.3390_3393delCTAT has not been reported in the literature in individuals affected with Fanconi Anemia Complementation Group J. However, c.3390_3393delCTAT has been reported in the literature in individuals affected with a variety of cancers such as Prostate (example, Hayano_2016); Breast (example, Li_2018, Vasmatzis_2020) and Pancreatic Cancer (example, Emelyanova_2022). Among these ascertained occurrences, it was reported in the germline DNA of an individual with Breast cancer (example Li_2018); as a putative germline variant due to its finding in the normal tissue of a an individual with Pancreatic Cancer (Emelyanova_2022); in settings of comprehensive genomic profiling on a liver biopsy along with other variation such as biallelic inactivation of TP53, CDH1, FOXA1, NIN and other structural rearrangements in which therapies targeting this specific mutation were invalidated over other validated therapies (Vasmatzis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported however another residue within this region (Threonine 1133) has been reported to be functionally relevant to BRIP1 function. The following publications have been ascertained in the context of this evaluation (PMID: 35309086, 27701467, 30385609, 31685261, 29368626). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for BRIP1 associated cancer predisposition but its association with a phenotype of autosomal recessive Fanconi Anemia Complementation Group J remains uncertain. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 28, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2023 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 119 amino acids are lost and replaced with 17 incorrect amino acids; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in an individual with prostate cancer (Hayano et al., 2016); This variant is associated with the following publications: (PMID: 22980975, 27701467, 29368626, 31685261, 30254378, 20159562, 21127055) - |
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Computational scores
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