chr17-58703201-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_058216.3(RAD51C):c.577C>T(p.Arg193Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,459,502 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R193R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 stop_gained
NM_058216.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.319
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-58703201-C-T is Pathogenic according to our data. Variant chr17-58703201-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58703201-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RAD51C | NM_058216.3 | c.577C>T | p.Arg193Ter | stop_gained | 4/9 | ENST00000337432.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RAD51C | ENST00000337432.9 | c.577C>T | p.Arg193Ter | stop_gained | 4/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251204Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135786
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GnomAD4 exome AF: 0.0000459 AC: 67AN: 1459502Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 726236
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22538716, 26740214, 25086635, 26261251, 23117857, 28588062, 22725699, 26720728, 25470109, 26681312, 26976419, 29093764, 29409816, 26689913, 32658311, 31589614, 28888541, 29922827, 34026625, 33077847, 33804961, 35626031, 34308104, 33999380) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 14, 2021 | This nonsense variant causes the premature termination of RAD51C protein synthesis. In addition, it has been reported in individuals/families with breast and/or ovarian cancer in the published literature (PMID: 32658311 (2021), 26976419 (2016), 26740214 (2016), 25086635 (2014), 22725699 (2013), 22538716 (2012)). Based on the available information, this variant is classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
| 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The p.R193* pathogenic mutation (also known as c.577C>T), located in coding exon 4 of the RAD51C gene, results from a C to T substitution at nucleotide position 577. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple families of different ethnicities with breast and/or ovarian cancer (Loveday C et al. Nat. Genet., 2012 Apr;44:475-6; author reply 476; Kushnir A et al. Breast Cancer Res Treat, 2012 Dec;136:869-74; Coulet F et al. Clin. Genet., 2013 Apr;83:332-6; Pennington KP et al. Clin Cancer Res, 2014 Feb;20:764-75; Blanco A et al. Breast Cancer Res Treat, 2014 Aug;147:133-43; Sopik V et al. Clin Genet, 2015 Oct;88:303-12; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Jønson L et al. Breast Cancer Res Treat, 2016 Jan;155:215-22; Susswein LR et al. Genet Med, 2016 08;18:823-32; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Li N et al. J Natl Cancer Inst, 2019 12;111:1332-1338; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in a patient with cutaneous melanoma and in an individual with multifocal paragangliomas and B-cell lymphocytosis with a family history of ovarian and colon cancer (Goyal A et al. JAAD Case Rep, 2019 Mar;5:240-241; Aoude LG et al. Sci Rep, 2020 10;10(1):17687). This alteration was shown to be susceptible to PARP inhibitors in mice, demonstrating loss of homologous repair pathway function (Kondrashova O et al. Cancer Discov, 2017 09;7:984-998). 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. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 19, 2023 | This variant changes 1 nucleotide in exon 4 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 observed in individuals affected with ovarian cancer (PMID: 22538716, 22725699, 26261251) and breast cancer (PMID: 25086635, 26740214, 26976419, 30949688, 32658311, 33471991). This variant has been identified in 10/251204 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. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
RAD51C-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 05, 2019 | The RAD51C c.577C>T (p.Arg193Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg193Ter variant has been reported in at least five studies in which it is found in a heterozygous state in seven individuals diagnosed with ovarian cancer, two of whom are related (Loveday et al. 2012; Coulet et al. 2013; Blanco et al. 2014; Song et al. 2015; Jonson et al. 2016). The p.Arg193Ter variant was also reported in a heterozygous state in two unaffected individuals who may yet be too young to develop disease (one individual was 25 years old and the other is of unknown age). All of these individuals have a family history of breast and/or ovarian cancer and are negative for variants in the BRCA1 and BRCA2 genes. The p.Arg193Ter variant was absent from 3,928 controls and is reported at a frequency of 0.00012 in the Latino population of the Genome Aggregation Database. Although the p.Arg193Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of disease penetrance and prevalence estimates. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg193Ter variant is classified as pathogenic for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 14, 2017 | Variant summary: The RAD51C c.577C>T (p.Arg193X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/120882 control chromosomes at a frequency of 0.0000414, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). Multiple publications have cited the variant in affected individuals, including a family that the variant cosegregated with disease (Blanco_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Fanconi anemia complementation group O Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Arg193*) 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 (rs200293302, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22538716, 22725699, 25086635, 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 140849). For these reasons, this variant has been classified as Pathogenic. - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 08, 2021 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
0.72, 0.72
ClinPred
D
GERP RS
Splicing
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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