rs369340666
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_032043.3(BRIP1):āc.1655T>Cā(p.Ile552Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,944 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I552V) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1655T>C | p.Ile552Thr | missense_variant | 12/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1655T>C | p.Ile552Thr | missense_variant | 12/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461720Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46AN XY: 727158
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 25, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, or colorectal cancer (PMID: 26315354, 26921362, 28135145, 34326862); This variant is associated with the following publications: (PMID: 26315354, 25980754, 26921362, 26689913, 28135145, 34326862, 38136308) - |
Familial cancer of breast Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2023 | The p.I552T variant (also known as c.1655T>C), located in coding exon 11 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1655. The isoleucine at codon 552 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov; 107(11)). This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces isoleucine with threonine at codon 552 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian, breast, uterine and colorectal cancer (PMID: 25980754, 26315354, 26689913, 26921362, 28135145), as well as in an unaffected individual (PMID: 26921362). This variant has been identified in 5/282702 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. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 552 of the BRIP1 protein (p.Ile552Thr). This variant is present in population databases (rs369340666, gnomAD 0.004%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer and/or colorectal polyps, ovarian cancer, and breast cancer (PMID: 25980754, 26315354, 26921362, 28135145). ClinVar contains an entry for this variant (Variation ID: 142965). 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. 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. - |
BRIP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The BRIP1 c.1655T>C variant is predicted to result in the amino acid substitution p.Ile552Thr. This variant has been reported in individuals with ovarian cancer (Ramus et al. 2015. PubMed ID: 26315354; Yurgelun et al. 2017. PubMed ID: 28135145), with Lynch syndrome-associated cancer and/or colorectal polyps (Supplemental Table 1 in Yurgelun et al. 2015. PubMed ID: 25980754; Supplementary Data 12 in Lu et al. 2015. PubMed ID: 26689913), with colorectal cancer (in Table A4 in Yurgelun et al. 2017. PubMed ID: 28135145), and with breast cancer (Supplemental Table 1 in Easton et al. 2016. PubMed ID: 26921362). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142965/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 05, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at