5-132595033-C-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):c.1958C>A(p.Ser653Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000353 in 1,612,458 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S653S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005732.4 stop_gained
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.1958C>A | p.Ser653Ter | stop_gained | 12/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1958C>A | p.Ser653Ter | stop_gained | 12/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250910Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135650
GnomAD4 exome AF: 0.0000377 AC: 55AN: 1460336Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 726646
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74312
ClinVar
Submissions by phenotype
Nijmegen breakage syndrome-like disorder Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2023 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 02-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 24, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Ser653*) 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 (rs587781904, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 32338768). ClinVar contains an entry for this variant (Variation ID: 141646). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The p.S653* pathogenic mutation (also known as c.1958C>A), located in coding exon 12 of the RAD50 gene, results from a C to A substitution at nucleotide position 1958. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration was observed in 1/1997 healthy controls and was not observed in 2000 breast cancer cases in one cohort (Thompson ER et al. J. Clin. Oncol. 2016 May;34(13):1455-9). 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. - |
RAD50-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2024 | The RAD50 c.1958C>A variant is predicted to result in premature protein termination (p.Ser653*). This variant has been observed in an individual with non-aggressive prostate, ovarian, breast cancer (Supplemental Table 1, Nguyen-Dumont et al. 2020. PubMed ID: 32338768; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Southey et al. 2021. PubMed ID: 34887416). This variant has been reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/141646/). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RAD50 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at