rs80358915
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000059.4(BRCA2):c.6901G>A(p.Glu2301Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,184 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 Uncertain significance (★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6901G>A | p.Glu2301Lys | missense_variant | Exon 12 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.6532G>A | p.Glu2178Lys | missense_variant | Exon 12 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6901G>A | non_coding_transcript_exon_variant | Exon 11 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1431184Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1AN XY: 713676
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 c.6901G>A variant (also known as p.E2301K), located in coding exon 11 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6901. The glutamic acid at codon 2301 is replaced by lysine, an amino acid with similar properties. In a study of 1854 high-risk breast and ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however this exon may be clinically dispensable based on partially retained homology directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). In addition, the literature describes a patient with a splice variant causing coding exon 11 skipping found in trans with a truncating BRCA2 variant in an individual without apparent Fanconi Anemia; although the degree of exon skipping is uncertain (Li L et al. Hum. Mutat., 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at