rs764803896
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP3_StrongPP5_Strong
The NM_032043.3(BRIP1):c.2119C>T(p.Arg707Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,288 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. R707G) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2119C>T | p.Arg707Cys | missense_variant | 15/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2119C>T | p.Arg707Cys | missense_variant | 15/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151996Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251042Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135694
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461292Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726996
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74220
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 08, 2021 | This missense variant replaces arginine with cysteine at codon 707 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). Functional studies have shown that this variant protein displays decreased helicase activity and fails to restore resistance to DNA interstrand crosslink (ICL)-inducing agents in BRIP1-deficient cells (PMID: 29788478, 33619228). This variant has been reported in an individual affected with Fanconi anemia complementation group J (PMID: 16116423). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 31822495, 33471991). This variant has been identified in 8/282390 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.R707C variant (also known as c.2119C>T), located in coding exon 14 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2119. The arginine at codon 707 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with Fanconi Anemia complementation group J (FA-J); however, limited information was provided (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5; George M et al. Hum Mutat. 2021 Dec;42:1648-1665). This alteration was detected in 1/1,199 ovarian cancer cases (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). In addition, functional studies suggest this variant partially impairs helicase activity compared to wild type (Bharti SK et al. Nucleic Acids Res. 2018 07;46:6238-6256). 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 24, 2021 | - - |
Familial cancer of breast Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 25, 2023 | - - |
Likely pathogenic, flagged submission | clinical testing | Mendelics | May 28, 2019 | - - |
Fanconi anemia complementation group J Pathogenic:1
Pathogenic, flagged submission | curation | Leiden Open Variation Database | Feb 07, 2011 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2024 | Variant summary: BRIP1 c.2119C>T (p.Arg707Cys) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2119C>T has been reported in the literature in individuals affected with Fanconi Anemia (Levitus_2005, George_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. At least one publication reports experimental evidence evaluating an impact on protein function and evaluated the variant as a hypomorphic change, however, does not allow convincing conclusions about the variant effect (Calvo_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33619228, 34585473, 16116423). ClinVar contains an entry for this variant (Variation ID: 234570). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 707 of the BRIP1 protein (p.Arg707Cys). This variant is present in population databases (rs764803896, gnomAD 0.007%). This missense change has been observed in individual(s) with Fanconi anemia, ovarian cancer (PMID: 16116423, 31822495). ClinVar contains an entry for this variant (Variation ID: 234570). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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 | Nov 12, 2018 | This variant is denoted BRIP1 c.2119C>T at the cDNA level, p.Arg707Cys (R707C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in an individual with Fanconi Anemia-J who also had a second BRIP1 missense variant and weak BRIP1 protein expression on Western blot analysis (Levitus 2005). However, as phase was not described, we cannot be certain that Arg707Cys was in trans with the second missense variant. In vitro functional assays suggests this variant partially impairs helicase activity compared to wild type (Bhari 2018). BRIP1 Arg707Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the helicase domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg707Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at