chr5-132595776-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_005732.4(RAD50):c.2173C>T(p.Arg725Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,612,366 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).
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2173C>T | p.Arg725Trp | missense_variant | Exon 13 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.1876C>T | p.Arg626Trp | missense_variant | Exon 14 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000225 AC: 56AN: 249438Hom.: 0 AF XY: 0.000156 AC XY: 21AN XY: 134848
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1460284Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 28AN XY: 726528
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74276
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This alteration is classified as likely 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. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 725 of the RAD50 protein (p.Arg725Trp). This variant is present in population databases (rs369560280, gnomAD 0.2%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24894818, 30262796). This missense change has been observed to co-occur in individuals with a different variant in RAD50 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 142505). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAD50 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
The RAD50 c.2173C>T (p.Arg725Trp) variant has been reported in women affected with or at-risk for breast cancer (PMID: 24894818 (2014), 30262796 (2018)). The frequency of this variant in the general population, 0.0015 (54/35406 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Benign:1
Variant summary: The RAD50 c.2173C>T (p.Arg725Trp) variant involves the alteration of a conserved nucleotide that is located in the RAD50, zinc hook domain (InterPro). 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 55/275042 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.001541 (53/34384). This frequency is about 25 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been cited in the literature, though it is unclear whether it was identified in breast cancer cases or control individuals (Damiola_2014; Young_2016). Two clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. Taken together, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at