17-61776429-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_032043.3(BRIP1):c.2069G>A(p.Gly690Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,948 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. G690A) has been classified as Uncertain significance.
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.2069G>A | p.Gly690Glu | missense_variant | 14/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2069G>A | p.Gly690Glu | missense_variant | 14/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74290
ClinVar
Submissions by phenotype
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 690 of the BRIP1 protein (p.Gly690Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma or breast cancer (PMID: 30414346; 31822495.). ClinVar contains an entry for this variant (Variation ID: 241637). 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. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2023 | The p.G690E variant (also known as c.2069G>A), located in coding exon 13 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2069. The glycine at codon 690 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in 1/101,759 breast cancer cases and 0/15,587 ovarian cancer cases. In this same study, using an inter-strand cross link damage survival assay, this alteration was found to be functionally abnormal (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This alteration has also been identified in 1/976 alleles from a cohort of Dutch melanomaprone families (Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464). In one study, this alteration was classified as a loss of function mutation based on its failure to confer resistance to either cisplatin or mitomycin C treatment (Calvo JA et al. Mol Cancer Res, 2021 06;19:1015-1025). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at