rs1305107535
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3_Moderate
The NM_032043.3(BRIP1):āc.2398T>Cā(p.Tyr800His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 1,447,606 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y800I?) has been classified as Likely pathogenic.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2398T>C | p.Tyr800His | missense_variant | 17/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2398T>C | p.Tyr800His | missense_variant | 17/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134392
GnomAD4 exome AF: 0.00000898 AC: 13AN: 1447606Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 2AN XY: 719412
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 07, 2023 | This missense variant replaces tyrosine with histidine at codon 800 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was identified in 1/60465 cases and 1/53460 controls - OR=0.884 (95%CI 0.055 to 14.136); p-value=1 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000414). This variant has been identified in 1/248420 chromosomes 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 | Sep 05, 2023 | The p.Y800H variant (also known as c.2398T>C), located in coding exon 16 of the BRIP1 gene, results from a T to C substitution at nucleotide position 2398. The tyrosine at codon 800 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 800 of the BRIP1 protein (p.Tyr800His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481618). 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) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at