13-32398289-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000059.4(BRCA2):c.9776T>C(p.Ile3259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9776T>C | p.Ile3259Thr | missense_variant | Exon 27 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9407T>C | p.Ile3136Thr | missense_variant | Exon 27 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1834T>C | non_coding_transcript_exon_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1834T>C | 3_prime_UTR_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.I3259T variant (also known as c.9776T>C), located in coding exon 26 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9776. The isoleucine at codon 3259 is replaced by threonine, an amino acid with similar properties. This amino acid position is not conserved however, threonine is a reference amino acid in several 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3259 of the BRCA2 protein (p.Ile3259Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 252418). 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) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at