rs28903086
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005732.4(RAD50):c.379G>A(p.Val127Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,613,908 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.379G>A | p.Val127Ile | missense_variant | Exon 4 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.82G>A | p.Val28Ile | missense_variant | Exon 5 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.00147 AC: 223AN: 152112Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00165 AC: 414AN: 251350Hom.: 4 AF XY: 0.00174 AC XY: 237AN XY: 135844
GnomAD4 exome AF: 0.00135 AC: 1967AN: 1461678Hom.: 4 Cov.: 31 AF XY: 0.00143 AC XY: 1039AN XY: 727146
GnomAD4 genome AF: 0.00146 AC: 222AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.00168 AC XY: 125AN XY: 74432
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Variant summary: The RAD50 c.379G>A (p.Val127Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 205/124248 control chromosomes (1 homozygote) at a frequency of 0.0016499, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported from case-control studies in literature. In a large case-control study, this variant was not associated with increased risk for breast cancer (Haiman_2013). 1/3 clinical diagnostic laboratories in ClinVar has classified this variant as likely benign. Taken together, this variant is classified as Benign. -
RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.379G>A at the cDNA level and p.Val127Ile (V127I) at the protein level, and results in the change of a Valine to a Isoleucine (GTC>ATC). RAD50 Val127Ile has been reported in two individuals with breast cancer in British studies and in two individuals with laryngeal cancer in a Polish study, but was also detected in at least five healthy controls (Tommiska 2006, Mosor 2010, Mosor 2013, Ziolkowska-Suchanek 2013). RAD50 Val127Ile was observed with an allele frequency of 0.1% in 1000 Genomes and at 0.2% and 0.05% in European and African Americans in the NHLBI Exome Sequencing Project respectively, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is highly 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. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. -
RAD50: BS2 -
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Nijmegen breakage syndrome-like disorder Uncertain:1Benign:1
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Hereditary cancer-predisposing syndrome Benign:2
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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. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at