chr17-61683354-A-C
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_032043.3(BRIP1):c.3692T>G(p.Ile1231Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. I1231M) has been classified as Likely benign.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
Publications
- familial ovarian cancerInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- Fanconi anemiaInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
- Fanconi anemia complementation group JInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- hereditary breast carcinomaInheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- colorectal adenomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250316 AF XY: 0.00000739 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459344Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726018 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1231 of the BRIP1 protein (p.Ile1231Arg). This variant is present in population databases (rs780578438, gnomAD 0.003%). 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: 1014384). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
not provided Uncertain:1
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.I1231R variant (also known as c.3692T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3692. The isoleucine at codon 1231 is replaced by arginine, an amino acid with similar properties. This amino acid position is not well 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at