rs876659847
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000059.4(BRCA2):c.4366G>A(p.Glu1456Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4366G>A | p.Glu1456Lys | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.3997G>A | p.Glu1333Lys | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.4366G>A | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243456Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131914
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1445770Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1AN XY: 716156
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
The p.E1456K variant (also known as c.4366G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4366. The glutamic acid at codon 1456 is replaced by lysine, an amino acid with similar properties. In a study of unselected Japanese breast cancer patients, this alteration was detected in 1/12490 male controls but not detected in 7051 breast cancer patients or in 11241 female controls (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is 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. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
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not provided Uncertain:1
This variant is denoted BRCA2 c.4366G>A at the cDNA level, p.Glu1456Lys (E1456K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 4594G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1456Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1456Lys occurs at a position that is not conserved and is located in a region of interaction with POLH and required for stimulation of POLH DNA polymerization activity (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Glu1456Lys is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1456 of the BRCA2 protein (p.Glu1456Lys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 232573). 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