rs760887592
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_032043.3(BRIP1):c.2464T>C(p.Tyr822His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,607,178 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. Y822C) 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.2464T>C | p.Tyr822His | missense_variant | 17/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2464T>C | p.Tyr822His | missense_variant | 17/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250042Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135232
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455026Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 723868
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2021 | This missense variant replaces tyrosine with histidine at codon 822 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). A functional study has shown that the variant protein partially rescued cells in response to DNA damage in a cell viability assay (PMID: 31822495). This variant has been reported in an individual affected with breast cancer (PMID: 31822495). This variant has been identified in 1/250042 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 | Oct 21, 2022 | The p.Y822H variant (also known as c.2464T>C), located in coding exon 16 of the BRIP1 gene, results from a T to C substitution at nucleotide position 2464. The tyrosine at codon 822 is replaced by histidine, an amino acid with similar properties. This alteration was detected in 1/101,759 breast cancer cases and 0/15,587 ovarian cancer cases, and in an inter-strand cross link damage survival assay, this alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). 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. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 822 of the BRIP1 protein (p.Tyr822His). This variant is present in population databases (rs760887592, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31822495). ClinVar contains an entry for this variant (Variation ID: 216788). 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 29, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at