rs780020495
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_032043.3(BRIP1):c.1741C>T(p.Arg581*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,848 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 stop_gained
NM_032043.3 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 0.936
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-61780893-G-A is Pathogenic according to our data. Variant chr17-61780893-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 434539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61780893-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRIP1 | NM_032043.3 | c.1741C>T | p.Arg581* | stop_gained | 12/20 | ENST00000259008.7 | NP_114432.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRIP1 | ENST00000259008.7 | c.1741C>T | p.Arg581* | stop_gained | 12/20 | 1 | NM_032043.3 | ENSP00000259008.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251446Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135898
GnomAD3 exomes
AF:
AC:
5
AN:
251446
Hom.:
AF XY:
AC XY:
4
AN XY:
135898
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727224
GnomAD4 exome
AF:
AC:
14
AN:
1461848
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
727224
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
1
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 03, 2021 | This nonsense variant causes the premature termination of BRIP1 protein synthesis, and has been reported in individuals affected with breast, colon, or liver cancer (PMIDs: 25186627 (2015), 27462233 (2016), 29368626 (2018), 29625052 (2018), and 32318955 (2020)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2024 | 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: 25186627, 27462233, 29368626, 33309985, 33619228, 33807840, 35171259, 35353237, 32318955, 29625052, 29922827, 29053726, 36451132) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Familial cancer of breast Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PS4_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 05, 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 | Apr 12, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2021 | This variant changes 1 nucleotide in exon 12 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 been reported in individuals affected with breast, colon and ovarian cancer in the literature (PMID: 25186627, 27462233, 29368626, 33807840). This variant has been identified in 5/251446 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 | Apr 29, 2022 | The p.R581* pathogenic mutation (also known as c.1741C>T), located in coding exon 11 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1741. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration was previously identified in a breast cancer patient (Tung N et al. Cancer. 2015 Jan;121(1):25-33). 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. - |
Ovarian neoplasm Pathogenic:2
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change creates a premature translational stop signal (p.Arg581*) 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 (rs780020495, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and colon cancer (PMID: 25186627, 27462233, 29368626). ClinVar contains an entry for this variant (Variation ID: 434539). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
BRIP1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2024 | The BRIP1 c.1741C>T variant is predicted to result in premature protein termination (p.Arg581*). This variant was reported germline/presumed germline in individuals with breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma, and colon cancer (Tung et al. 2015. PubMed ID: 25186627; Harter et al. 2017. PubMed ID: 29053726; Zeng et al. 2020. PubMed ID: 32318955; Yin et al. 2022. PubMed ID: 35171259; Sorscher. 2016. PubMed ID: 27462233; Inagaki et al. 2021. PubMed ID: 33807840; Felix et al. 2022. PubMed ID: 35353237). This variant was also reported in prostate adenocarcinoma, hepatocellular carcinoma, and ovarian cancer samples (Calvo et al. 2021. PubMed ID: 33619228; Huang et al. 2018. PubMed ID: 29625052; Feng et al. 2021. PubMed ID: 33842585). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and documented as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/434539/). Nonsense variants in BRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Breast cancer, early-onset Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at