chr17-61793626-T-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_032043.3(BRIP1):c.1444A>G(p.Ile482Val) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,608,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. I482M) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1444A>G | p.Ile482Val | missense_variant | 10/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1444A>G | p.Ile482Val | missense_variant | 10/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000493 AC: 12AN: 243548Hom.: 0 AF XY: 0.0000457 AC XY: 6AN XY: 131432
GnomAD4 exome AF: 0.000111 AC: 161AN: 1455972Hom.: 1 Cov.: 30 AF XY: 0.0000939 AC XY: 68AN XY: 723888
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 09, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25980754, 28873162, 26921362, Whitaker2020[abstract]) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2016 | Variant summary: The BRIP1 c.1444A>G (p.Ile482Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 3/88242 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000658 (3/45614). This frequency is greater than the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was cited in 1 patient with a history of Lynch syndrome-associated cancer and/or polyps; however, co-segregation studies were not done, and thus it cannot be concluded that this variant was causative in this patient. Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 04, 2023 | This missense variant replaces isoleucine with valine at codon 482 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, colorectal cancer (Whitaker 2020, DOI: 10.1200/JCO.2020.38.15) and suspected Lynch syndrome (PMID: 25980754), as well as in unaffected individuals (PMID: 26921362; Whitaker 2020; FLOSSIES, https://whi.color.com/). This variant has been identified in 15/274942 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 | curation | Sema4, Sema4 | Aug 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2022 | The p.I482V variant (also known as c.1444A>G), located in coding exon 9 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1444. The isoleucine at codon 482 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was identified in a control population (Easton DF et al. J Med Genet, 2016 May;53:298-309). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 | Sep 08, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 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 | 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 | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 482 of the BRIP1 protein (p.Ile482Val). This variant is present in population databases (rs142744352, gnomAD 0.01%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 128160). 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. - |
Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 03, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at