17-61685976-A-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_032043.3(BRIP1):āc.2765T>Gā(p.Leu922Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L922L) has been classified as Likely benign.
Frequency
Consequence
NM_032043.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2765T>G | p.Leu922Ter | stop_gained | 19/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2765T>G | p.Leu922Ter | stop_gained | 19/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251392Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461762Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727178
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26315354, 25452441, 26921362, 28152038, 29368626, 29308099, 31980526, 29922827, 33804961, 35022142) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jul 29, 2022 | PVS1, PS4, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 05, 2023 | The BRIP1 c.2765T>G (p.Leu922*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 25452441 (2015), 26921362 (2016), 29368626 (2018), and 33471991 (2021)), in an individual with testicular, prostate, and bladder cancer (PMDI: 35022142 (2022)), and in unaffected controls (PMIDs: 26315354 (2015), 34887416 (2021), 33804961 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ BRIP1)). The frequency of this variant in the general population, 0.000026 (3/113686 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 25, 2020 | This variant changes 1 nucleotide in exon 19 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in an individual affected with triple negative breast cancer (PMID: 25452441) and an unaffected control in an ovarian cancer case-control study (PMID: 26315354). This variant has been identified in 3/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2021 | The p.L922* pathogenic mutation (also known as c.2765T>G), located in coding exon 18 of the BRIP1 gene, results from a T to G substitution at nucleotide position 2765. This changes the amino acid from a leucine to a stop codon within coding exon 18. This mutation has been identified in a cohort of unselected patients with triple negative breast cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), in 0/3236 cases with invasive epithelial ovarian cancer and in 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107), and in 1/13213 breast cancer cases and 0/5242 controls from the UK (Easton DF et al. J Med Genet, 2016 05;53:298-309). 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 23, 2018 | - - |
Familial cancer of breast Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 01, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Leu922*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs587782410, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25452441, 26921362). ClinVar contains an entry for this variant (Variation ID: 142366). For these reasons, this variant has been classified as Pathogenic. - |
Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Ovarian neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 25, 2016 | Variant summary: The BRIP1 c.2765T>G (p.Leu922X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121394, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant has been reported in one triple negative breast cancer case as well as a high-risk unaffected control (Couch_2015, Ramus_2015) via publications. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." However, it does need to be noted, a recent publication by Easton_2016 (PMID: 26921362) indicates that the prevalence of truncating variants in BRIP1 have comparable occurrences in controls and cases, for example, p.Arg798Ter was observed in 23 cases and 18 controls, suggesting that truncating variants may not be associated with a substantial increase in breast cancer risk, although the authors do state "BRIP1 screening might have utility for ovarian cancer risk prediction, in combination with other risk factors." Therefore, the variant of interest has been classified as "Likely Pathogenic." - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at