17-58703254-T-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_058216.3(RAD51C):c.630T>G(p.Tyr210*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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
Consequence
NM_058216.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This variant is denoted RAD51C c.630T>G at the cDNA level and p.Tyr210Ter (Y210X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least one individual undergoing multi-gene panel testing (LaDuca 2017) and is considered pathogenic. -
The RAD51C c.630T>G (p.Tyr210*) variant causes the premature termination of RAD51C protein synthesis. This variant has been reported in the published literature in an individual with ovarian cancer (PMID: 30128536 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.Y210* pathogenic mutation (also known as c.630T>G) located in coding exon 4 of the RAD51C gene, results from a T to G substitution at nucleotide position 630. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. 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. -
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 reported in an individual affected with ovarian cancer (PMID: 30128536). 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 Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Breast and/or ovarian cancer Pathogenic:1
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Variant summary: RAD51C c.630T>G (p.Tyr210X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251252 control chromosomes (gnomAD) but has been reported in the literature in an individual affected with ovarian cancer (Lu_2018) and an unknown phenotype (LaDuca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Fanconi anemia complementation group O Pathogenic:1
This sequence change creates a premature translational stop signal (p.Tyr210*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 185074). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at