17-58732512-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_058216.3(RAD51C):c.994C>T(p.Gln332*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,178 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
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.13
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 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 0.121 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 17-58732512-C-T is Pathogenic according to our data. Variant chr17-58732512-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461178Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726970
GnomAD4 exome
AF:
AC:
1
AN:
1461178
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
726970
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2020 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost including the nuclear localization signal (French 2003); Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history including ovarian and breast cancers (Kraus 2017); This variant is associated with the following publications: (PMID: 27616075) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 30, 2019 | The variant is predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality (0/281382 chr). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2024 | The p.Q332* variant (also known as c.994C>T), located in coding exon 8 of the RAD51C gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration occurs at the 3' terminus of theRAD51C gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this variant is predicted to truncate the C-terminal region of the protein including the terminal end of the RECA domain (Magrane M et al. Database (Oxford) 2011). This alteration has been detected in an ovarian cancer patient diagnosed at age 63 who had a sister diagnosed with breast cancer at age 46 (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 25, 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 nuclear localization signal (PMID: 12966089). To our knowledge, functional studies have not been reported for this variant. A functional study has reported that a truncation of the last 11 amino acids of the RAD51C protein partially reduced nuclear localization and ability to rescue sensitivity to mitomycin C treatment in RAD51C-deficient cell (PMID: 12966089). This variant has been reported in an individual affected with bilateral ovarian cancer (PMID: 27616075). 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 | Oct 28, 2024 | This sequence change creates a premature translational stop signal (p.Gln332*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 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: 27616075). ClinVar contains an entry for this variant (Variation ID: 486279). This variant disrupts a region of the RAD51C protein in which other variant(s) (p.Ser353Hisfs*8) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
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
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at