rs140233356
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032043.3(BRIP1):c.2830C>T(p.Gln944Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q944Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
BRIP1
NM_032043.3 stop_gained
NM_032043.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.66
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-61685911-G-A is Pathogenic according to our data. Variant chr17-61685911-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2830C>T | p.Gln944Ter | stop_gained | 19/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2830C>T | p.Gln944Ter | stop_gained | 19/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251292Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135824
GnomAD3 exomes
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1
AN:
251292
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1
AN XY:
135824
Gnomad AFR exome
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GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
AF:
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1
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 22, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2022 | This sequence change creates a premature translational stop signal (p.Gln944*) 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 (rs140233356, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 487435). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2023 | The p.Q944* pathogenic mutation (also known as c.2830C>T), located in coding exon 18 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2830. This changes the amino acid from a glutamine to a stop codon within coding exon 18. 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. - |
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
Uncertain
D
MutationTaster
Benign
A;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