rs876659874
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_058216.3(RAD51C):c.914G>A(p.Trp305*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 stop_gained
NM_058216.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.47
Genes affected
RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58724049-G-A is Pathogenic according to our data. Variant chr17-58724049-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460588Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726686
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.W305* pathogenic mutation (also known as c.914G>A), located in coding exon 7 of the RAD51C gene, results from a G to A substitution at nucleotide position 914. This changes the amino acid from a tryptophan to a stop codon within coding exon 7. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2020 | This variant changes 1 nucleotide in exon 7 of the RAD51C gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with ovarian cancer (PMID: 30322717). This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 27, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 28, 2022 | PVS1, PM2, PS4_Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2017 | This variant is denoted RAD51C c.914G>A at the cDNA level and p.Trp305Ter (W305X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 04, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. - |
Fanconi anemia complementation group O Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 18, 2023 | This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 232614). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp305*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2019 | - - |
RAD51C-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2023 | The RAD51C c.914G>A variant is predicted to result in premature protein termination (p.Trp305*). This variant was reported in individuals with ovarian cancer (Supplemental Table 1, Carter et al 2018. PubMed ID: 30322717) and breast cancer (Supplementary Table 3, Palmer et al 2020. PubMed ID: 32427313; Table 1, Bagherzadeh et al 2020. PubMed ID: 32809180). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56801410-G-A). This variant is interpreted as pathogenic by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/232614/). Nonsense variants in RAD51C are expected to be pathogenic (Meindl et al 2010. PubMed ID: 20400964). Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at