rs587780875
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032043.3(BRIP1):c.1383T>G(p.Tyr461Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,610,654 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y461Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_032043.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1383T>G | p.Tyr461Ter | stop_gained | 10/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1383T>G | p.Tyr461Ter | stop_gained | 10/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247830Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133920
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458492Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725512
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 14, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 216130). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr461*) 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). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2015 | This pathogenic variant is denoted BRIP1 c.1383T>G at the cDNA level and p.Tyr461Ter (Y461X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. The presence of a BRIP1 pathogenic variant may confer an increased risk for female breast and ovarian cancer, and possibly pancreatic (Seal 2006, Rafnar 2011, Pennington 2014). In a case-control study of BRCA-negative women with breast cancer, truncating BRIP1 pathogenic variants were identified in 0.7% (9/1,212) women with breast cancer and 0.1% (2/2,081) controls, suggesting some increased breast cancer risk (OR = 2.0, p=0.012) (Seal 2006). Pennington et al. (2014) also identified germline BRIP1 pathogenic variants in 1.1% (4/367) patients with ovarian cancer, peritoneal cancer or fallopian tube cancer. It has been hypothesized that BRIP1 may be a low penetrance allele as families with multiple cases of breast cancer found to harbor a BRIP1 pathogenic variant have shown incomplete segregation with disease (Seal 2006). Fanconi anemia (FA) is a rare autosomal recessive condition that can be caused by two pathogenic variants (one in each copy of the gene) in the BRIP1 gene (Seal 2006). This condition is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy in children including leukemia and certain solid tumors. The Fanconi anemia phenotype due to BRIP1 pathogenic variants is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 pathogenic variants (Apostolou 2013). If both parents carry a BRIP1 pathogenic variant, the risk to have a child with FA is 25% for each pregnancy. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2020 | The p.Y461* pathogenic mutation (also known as c.1383T>G), located in coding exon 9 of the BRIP1 gene, results from a T to G substitution at nucleotide position 1383. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at