rs768555161
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_032043.3(BRIP1):c.2329C>T(p.Arg777Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,572 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. R777G) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2329C>T | p.Arg777Cys | missense_variant | 16/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2329C>T | p.Arg777Cys | missense_variant | 16/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152054Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251302Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135816
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461572Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727104
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74268
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2021 | Observed in individuals with breast or ovarian cancer (Moyer 2020); Published functional studies suggest a damaging effect: unable to rescue DNA damage repair in BRIP1-null cells (Moyer 2020); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25344691, 31822495) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 06, 2023 | In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 31822495 (2020), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1)). This variant has been reported to have a deleterious effect on BRIP1 protein function, however further studies are required to validate this finding (PMID: 31822495 (2020)). The frequency of this variant in the general population, 0.000012 (3/251302 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 10, 2019 | This missense variant replaces arginine with cysteine at codon 777 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251302 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 | May 28, 2024 | The p.R777C variant (also known as c.2329C>T), located in coding exon 15 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2329. The arginine at codon 777 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, the p.R777C 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, the p.R777C alteration was found to be functionally abnormal (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This alteration was identified in an individual diagnosed with Fanconi anemia (George M et al. Hum Mutat, 2021 Dec;42:1648-1665). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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 | Aug 08, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 777 of the BRIP1 protein (p.Arg777Cys). This variant is present in population databases (rs768555161, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 31822495). ClinVar contains an entry for this variant (Variation ID: 185165). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at