rs1060501954
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):βc.1253_1254delβ(p.Phe418CysfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000696 in 1,580,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. F418F) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.1253_1254del | p.Phe418CysfsTer13 | frameshift_variant | 9/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1253_1254del | p.Phe418CysfsTer13 | frameshift_variant | 9/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000852 AC: 2AN: 234674Hom.: 0 AF XY: 0.00000786 AC XY: 1AN XY: 127212
GnomAD4 exome AF: 0.00000630 AC: 9AN: 1428160Hom.: 0 AF XY: 0.00000845 AC XY: 6AN XY: 710182
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2022 | The c.1253_1254delTT pathogenic mutation, located in coding exon 9 of the RAD50 gene, results from a deletion of two nucleotides at nucleotide positions 1253 to 1254, causing a translational frameshift with a predicted alternate stop codon (p.F418Cfs*13). This mutation was identified in one individual from a cohort of 291 patients with triple negative breast cancer (Hahnen E et al. JAMA Oncol, 2017 Oct;3:1378-1385). This alteration was identified in 1/278 individuals from a cohort BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). Of note, this alteration is also designated as "c.1252delTT" and "c.1253_1254del" in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | clinical testing | Invitae | Sep 06, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.004%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 408373). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This sequence change creates a premature translational stop signal (p.Phe418Cysfs*13) 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). - |
Nijmegen breakage syndrome-like disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at