rs144253015
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_005732.4(RAD50):c.3455G>A(p.Arg1152Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,611,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1152L) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3455G>A | p.Arg1152Gln | missense_variant | 22/25 | ENST00000378823.8 | |
TH2LCRR | NR_132124.1 | n.153+978C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3455G>A | p.Arg1152Gln | missense_variant | 22/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000224 AC: 34AN: 152024Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000954 AC: 24AN: 251442Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135888
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1459830Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726248
GnomAD4 genome AF: 0.000223 AC: 34AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2014 | RAD50 has only been recently described in association with cancer predisposition and the risks are not well understood.This variant is denoted RAD50 c.3455G>A at the cDNA level, p.Arg1152Gln (R1152Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg1152Gln was observed with an allele frequency of 0.2% (11/4406) in African Americans in the NHLBI Exome Sequencing Project, which is not frequent enough to be considered a common benign variant. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is fully conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function but lean toward benign. The currently available evidence about this variant does not allow us to predict whether RAD50 Arg1152Gln is a pathogenic variant or a benign variant, and it is therefore classified as having unknown significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
RAD50-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2022 | The RAD50 c.3455G>A variant is predicted to result in the amino acid substitution p.Arg1152Gln. This variant was reported in an individual with breast or Lynch syndrome (Table S1 - Velázquez et al. 2020. PubMed ID: 32522261). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131972872-G-A). In ClinVar this variant has conflicting interpretations of pathogenicity of benign, likely benign, and uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/128019/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Nijmegen breakage syndrome-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 23, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at