5-132591957-CA-CAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005732.4(RAD50):c.1722dup(p.Gln575ThrfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N572N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005732.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.1722dup | p.Gln575ThrfsTer3 | frameshift_variant | 11/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1722dup | p.Gln575ThrfsTer3 | frameshift_variant | 11/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151732Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251222Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135796
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459682Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726280
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151732Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74070
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Gln575Thrfs*3) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 16385572, 19409520, 24763289). ClinVar contains an entry for this variant (Variation ID: 142556). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2023 | The c.1722dupA pathogenic mutation, located in coding exon 11 of the RAD50 gene, results from a duplication of A at nucleotide position 1722, causing a translational frameshift with a predicted alternate stop codon (p.Q575Tfs*3). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2013 | Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) - |
Nijmegen breakage syndrome-like disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 25, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 25, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 10, 2023 | This frameshift variant alters the translational reading frame of the RAD50 mRNA and causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251222 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual undergoing hereditary cancer predisposition testing (PMID: 24763289 (2014)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: RAD50 c.1722dupA (p.Gln575ThrfsX3) 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 allele was found at a frequency of 4e-06 in 251222 control chromosomes. c.1722dupA has been reported in the literature in individuals affected with breast cancer (e.g. Bucalo_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37262986). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at