13-32316523-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
The ENST00000530893.7(BRCA2):c.-303A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000530893.7 splice_region
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 |
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BRCA2 | ENST00000530893.7 | c.-303A>G | splice_region_variant | Exon 2 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000380152.8 | c.63A>G | p.Lys21Lys | synonymous_variant | Exon 2 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893 | c.-303A>G | 5_prime_UTR_variant | Exon 2 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.63A>G | non_coding_transcript_exon_variant | Exon 1 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461360Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727014
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant summary: BRCA2 c.63A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251130 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.63A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
The c.63A>G variant (also known as p.K21K), located in coding exon 1 of the BRCA2 gene, results from an A to G substitution at nucleotide position 63. This nucleotide substitution does not change the lysine at codon 21. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -
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Breast neoplasm Uncertain:1
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BRCA2-related cancer predisposition Benign:1
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at