rs81002821
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000059.4(BRCA2):c.6842-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,311,170 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 splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.6842-14A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6842-14A>G | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240564Hom.: 0 AF XY: 0.00000764 AC XY: 1AN XY: 130904
GnomAD4 exome AF: 0.00000153 AC: 2AN: 1311170Hom.: 0 Cov.: 21 AF XY: 0.00000303 AC XY: 2AN XY: 659274
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2022 | Variant summary: BRCA2 c.6842-14A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/3 computational tools predict no significant impact on normal splicing. However, a recent publication reported experimental evidence, demonstrating in a mini-gene assay that this variant resulted in an in-frame skipping of exon 12, in ~75% of the transcripts (Meulemans_2020). On the other hand, the same study also revealed that in-frame skipping of exon 12 leads to the deletion of a potentially dispensable 32-amino acid sequence, as E12-deleted BRCA2 protein led to a partially functional protein that was able to complement the loss of endogenous wild-type Brca2 in a mouse embryonic stem cell (mESC)-based functional assay (Meulemans_2020). The variant allele was found at a frequency of 7.4e-06 in 271952 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6842-14A>G in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome has been reported. Co-occurrences with other pathogenic variants have been reported (PALB2 c.2218C>T (p.Q740X) and BRCA2 c.3076_3077delAA (p.Lys1026GlufsX9) in two internal LCA samples), providing supporting evidence for a benign role. Another clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 11, 2018 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at