rs1555605103
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_058216.3(RAD51C):c.1018C>T(p.Gln340*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,004 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RAD51C
NM_058216.3 stop_gained
NM_058216.3 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 0.187
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 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0999 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58732536-C-T is Pathogenic according to our data. Variant chr17-58732536-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.1018C>T | p.Gln340* | stop_gained | 8/9 | ENST00000337432.9 | NP_478123.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.1018C>T | p.Gln340* | stop_gained | 8/9 | 1 | NM_058216.3 | ENSP00000336701.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460004Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726446
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2022 | The p.Q340* variant (also known as c.1018C>T), located in coding exon 8 of the RAD51C gene, results from a C to T substitution at nucleotide position 1018. This changes the amino acid from a glutamine to a stop codon. This variant was detected in a cohort of 7768 adult ovarian cancer cases of European ancestry (Lilyquist J et al. Gynecol Oncol, 2017 11;147:375-380). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus within coding exon 8, which is the penultimate exon of the gene, and is not expected to trigger nonsense-mediated mRNA decay. However, this variant is predicted to truncate the C-terminal region of the protein including the terminal end of the RECA domain and a nuclear localization signal (NLS) (Magrane M, et al. Database (Oxford) 2011). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 26, 2020 | This variant changes 1 nucleotide in exon 8 of the RAD51C gene, creating a translation stop signal. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the C-terminal portion of ATPase domain (a.a. 100-347) (PMID: 1731253) and binding domain to other RAD51 paralogs (a.a. 79-376) (PMID: 14704354), as well as nuclear localization signal (a.a. 366-370) (PMID: 12966089). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, splice site and deletion variants that disrupt the last exon 9, encoding a.a. 343-376, have been reported in individuals affected with ovarian cancer (PMID: 26270727, Color internal data, communication with external laboratory). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Fanconi anemia complementation group O Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2023 | This sequence change creates a premature translational stop signal (p.Gln340*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the RAD51C protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 486270). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the RAD51C protein, which is important for proper localization and function of the RAD51C protein (PMID:12966089). While functional studies have not been performed to directly test the effect of this variant on RAD51C protein function, this suggests that disruption of this region of the protein is causative of disease. 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. - |
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
ClinPred
D
GERP RS
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 8
Find out detailed SpliceAI scores and Pangolin per-transcript scores at