rs768793789
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_058216.3(RAD51C):c.525dup(p.Cys176LeufsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 frameshift
NM_058216.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.98
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 17-58696811-G-GC is Pathogenic according to our data. Variant chr17-58696811-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 409827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.525dup | p.Cys176LeufsTer27 | frameshift_variant | 3/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.525dup | p.Cys176LeufsTer27 | frameshift_variant | 3/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251468Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135910
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727226
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Sep 13, 2022 | PVS1, PS4, PM2_SUP - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Nov 02, 2014 | Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2020 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 02, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 04, 2023 | Criteria applied: PVS1,PS4_MOD,PM2_SUP - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 15, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 02, 2021 | The c.525dupC pathogenic mutation, located in coding exon 3 of the RAD51C gene, results from a duplication of C at nucleotide position 525, causing a translational frameshift with a predicted alternate stop codon (p.C176Lfs*27). In a study of 1100 German high-risk breast and/or ovarian cancer families, this alteration was detected in 2 individual(s) (Meindl A et al. Nat Genet, 2010 May;42:410-4). In a study of 10,389 adult cancers, this alteration was identified in a 78 year old individual with lung adenocarcinoma (Huang KL et al. Cell, 2018 04;173:355-370.e14). In addition to the clinical data presented in the literature, 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. - |
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Fanconi anemia complementation group O Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | This sequence change creates a premature translational stop signal (p.Cys176Leufs*27) 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). This variant is present in population databases (rs768793789, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer, non-Hodgkin lymphoma and ovarian cancer (PMID: 20400964). This variant is also known as c.525_526insC. ClinVar contains an entry for this variant (Variation ID: 409827). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at