chr13-32362524-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_000059.4(BRCA2):c.7807G>C(p.Ala2603Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7807G>C | p.Ala2603Pro | missense_variant, splice_region_variant | Exon 17 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7438G>C | p.Ala2480Pro | missense_variant, splice_region_variant | Exon 17 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7815G>C | non_coding_transcript_exon_variant | Exon 16 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:1
Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C25), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (32) (PP3-sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.995 and an overall classification of pathogenic (PS3_strong). Data not used in classification: There are conflicting in silico predictions of pathogenicity; AlignGVGD (class: C25), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (32). There are additional reports of this variant in UMD (1). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at