rs876658934
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_032043.3(BRIP1):c.2372A>T(p.Asp791Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,908 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D791E) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2372A>T | p.Asp791Val | missense_variant | 16/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2372A>T | p.Asp791Val | missense_variant | 16/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727148
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 08, 2024 | This missense variant replaces aspartic acid with valine at codon 791 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant altered the protein's ability to repair interstrand cross-link damage (PMID: 31822495). This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354) and an individual affected with early-onset breast cancer (PMID: 31822495). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2022 | The p.D791V variant (also known as c.2372A>T), located in coding exon 15 of the BRIP1 gene, results from an A to T substitution at nucleotide position 2372. The aspartic acid at codon 791 is replaced by valine, an amino acid with highly dissimilar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107:). In an inter-strand cross link damage survival assay, the p.D791V alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 791 of the BRIP1 protein (p.Asp791Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer and breast cancer (PMID: 26315354, 31822495). ClinVar contains an entry for this variant (Variation ID: 231061). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2018 | This variant is denoted BRIP1 c.2372A>T at the cDNA level, p.Asp791Val (D791V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant has been observed in at least one individual with serous ovarian cancer (Ramus 2015). BRIP1 Asp791Val was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Asp791Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
not specified Benign:1
Benign, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at