NM_000059.4:c.7007+2T>C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000059.4(BRCA2):c.7007+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000138 in 1,450,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7007+2T>C | splice_donor_variant, intron_variant | Intron 13 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.6638+2T>C | splice_donor_variant, intron_variant | Intron 13 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.7007+2T>C | splice_donor_variant, intron_variant | Intron 12 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450840Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 721912
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change affects a donor splice site in intron 13 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 531318). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.7007+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 12 in the BRCA2 gene. This alteration was identified in 1/3310 female patients who underwent BRCA1/2 testing in the Netherlands (Teixeira N et al. Eur J Hum Genet, 2018 06;26:848-857). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). 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