17-35118499-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002878.4(RAD51D):c.263+2T>C variant causes a splice donor, intron 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_002878.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.263+2T>C | splice_donor_variant, intron_variant | Intron 3 of 9 | 1 | NM_002878.4 | ENSP00000338790.6 | |||
ENSG00000267618 | ENST00000593039.5 | c.3+2792T>C | intron_variant | Intron 1 of 6 | 2 | ENSP00000466834.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
The TP53 mutation takes place in the coding region of exon 8. This gene is one of the master components of the apoptotic cycle. The mutation does not lead to any structural change due to the absence of premature chain termination rather there is p. Arg273Cys substitution, which weakens the interaction of the TP53 to the Damaged DNA due to the weakening of the salt bridge, which could also lead to spoptotic disregulation. Hence, being classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1
In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in RAD51D are known to be pathogenic (PMID: 21822267). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in an individual with a RAD51D-related disease. However, a different variant (c.263+1G>A) affecting the same donor splice site has been reported in a patient with familial ovarian cancer (PMID: 26261251) This sequence change affects a donor splice site in intron 3 of the RAD51D gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at