17-58703195-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_058216.3(RAD51C):c.572-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,254 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 Likely pathogenic (★★).
Frequency
Consequence
NM_058216.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.572-1G>C | splice_acceptor_variant | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.572-1G>C | splice_acceptor_variant | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459254Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726170
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1_STR, PS4_SUP, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Oct 24, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 15, 2023 | This variant causes a G>C nucleotide substitution at the -1 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A minigene splicing assay has shown that this variant resulted in the out-of-frame skipping of exon 4 (PMID: 35740625). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). Different substitutions in canonical splice site positions at this acceptor site, c.572-1G>T and c.572-2A>G, have been reported in one individual each affected with breast cancer or ovarian cancer (PMID: 27908594, 30949688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2023 | The c.572-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 4 of the RAD51C gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. As such, this alteration is classified as likely pathogenic. - |
Fanconi anemia complementation group O Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change affects an acceptor splice site in intron 3 of the RAD51C 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 RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast or ovarian cancer (PMID: 26261251, 28888541, 32107557). ClinVar contains an entry for this variant (Variation ID: 480497). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 20, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at