rs730881623
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_032043.3(BRIP1):c.394A>T(p.Thr132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. T132N) has been classified as Likely benign.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.394A>T | p.Thr132Ser | missense_variant | 5/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.394A>T | p.Thr132Ser | missense_variant | 5/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152014Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251004Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135714
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1460630Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21AN XY: 726684
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 26, 2022 | This missense variant replaces threonine with serine at codon 132 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, but also in control individuals (PMID: 33471991). This variant has been identified in 7/282388 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 03, 2022 | The p.T132S variant (also known as c.394A>T), located in coding exon 4 of the BRIP1 gene, results from an A to T substitution at nucleotide position 394. The threonine at codon 132 is replaced by serine, an amino acid with similar properties.This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 28, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2022 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 132 of the BRIP1 protein (p.Thr132Ser). This variant is present in population databases (rs730881623, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182331). 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 not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 20, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer as well as healthy controls (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at