rs367925756
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The ENST00000378823.8(RAD50):c.2047G>A(p.Val683Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
ENST00000378823.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.2047G>A | p.Val683Ile | missense_variant | 13/25 | ENST00000378823.8 | NP_005723.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2047G>A | p.Val683Ile | missense_variant | 13/25 | 1 | NM_005732.4 | ENSP00000368100 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251334Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135838
GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461806Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54AN XY: 727206
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
Nijmegen breakage syndrome-like disorder Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 09, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 683 of the RAD50 protein (p.Val683Ile). This variant is present in population databases (rs367925756, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818). ClinVar contains an entry for this variant (Variation ID: 185548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2022 | The p.V683I variant (also known as c.2047G>A), located in coding exon 13 of the RAD50 gene, results from a G to A substitution at nucleotide position 2047. The valine at codon 683 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in 1/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). It was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Lung sarcomatoid carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Salgia Laboratory, City of Hope | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at