rs786201789
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):βc.2202delβ(p.Met735Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,602,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P734P) 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.2202del | p.Met735Ter | frameshift_variant | 13/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2202del | p.Met735Ter | frameshift_variant | 13/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000814 AC: 2AN: 245594Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133246
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1450356Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2AN XY: 722216
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74316
ClinVar
Submissions by phenotype
Nijmegen breakage syndrome-like disorder Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 24, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | The c.2202delC pathogenic mutation (also known as p.M735*), located in coding exon 13 of the RAD50 gene, results from a deletion of one nucleotide at position 2202. This changes the amino acid from a methionine to a stop codon within coding exon 13. 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 | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Met735*) 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 present in population databases (rs769230013, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 184917). For these reasons, this variant has been classified as Pathogenic. - |
RAD50-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 18, 2024 | The RAD50 c.2202delC variant is predicted to result in premature protein termination (p.Met735*). This variant was reported in individuals with breast and/or ovarian cancer (Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Table S2, Espinel et al. 2022. PubMed ID: 35626031). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131931494-GC-G) and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184917/). This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 30, 2023 | This nonsense variant is predicted to cause the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.000011 (3/276904 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has not been reported in individuals with RAD50-related conditions in the published literature. Based on the available information, this variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at