17-61780290-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.1906G>A(p.Glu636Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E636V) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.E636K variant (also known as c.1906G>A), located in coding exon 12 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1906. The glutamic acid at codon 636 is replaced by lysine, an amino acid with similar properties. In an inter-strand cross link damage survival assay, the p.E636K 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. -
This missense variant replaces glutamic acid with lysine at codon 636 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. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 636 of the BRIP1 protein (p.Glu636Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset breast cancer (PMID: 31822495). ClinVar contains an entry for this variant (Variation ID: 407854). Invitae Evidence 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 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. -
not provided Uncertain:1
Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer (Weber-Lassalle 2018); This variant is associated with the following publications: (PMID: 29368626, 31822495) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at