5-132608717-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):c.2821C>T(p.Gln941*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000885 in 1,582,112 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q941Q) 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2821C>T | p.Gln941* | stop_gained | Exon 17 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.2524C>T | p.Gln842* | stop_gained | Exon 18 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000145 AC: 3AN: 207334Hom.: 0 AF XY: 0.00000898 AC XY: 1AN XY: 111302
GnomAD4 exome AF: 0.00000909 AC: 13AN: 1430072Hom.: 0 Cov.: 31 AF XY: 0.0000113 AC XY: 8AN XY: 708874
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74248
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.Q941* pathogenic mutation (also known as c.2821C>T), located in coding exon 17 of the RAD50 gene, results from a C to T substitution at nucleotide position 2821. This changes the amino acid from a glutamine to a stop codon within coding exon 17. This variant was reported in 4/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
This sequence change creates a premature translational stop signal (p.Gln941*) 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 (rs397507177, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hereditary cancer (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 37376). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
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Nijmegen breakage syndrome-like disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at