rs149217423
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_005732.4(RAD50):āc.1336A>Gā(p.Lys446Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,613,074 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
Genomes: š 0.00022 ( 0 hom., cov: 32)
Exomes š: 0.00032 ( 0 hom. )
Consequence
RAD50
NM_005732.4 missense
NM_005732.4 missense
Scores
5
5
9
Clinical Significance
Conservation
PhyloP100: 8.86
Genes affected
RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.22081736).
BP6
Variant 5-132589721-A-G is Benign according to our data. Variant chr5-132589721-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140939.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1336A>G | p.Lys446Glu | missense_variant | Exon 9 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.1039A>G | p.Lys347Glu | missense_variant | Exon 10 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000264 AC: 66AN: 250474Hom.: 0 AF XY: 0.000288 AC XY: 39AN XY: 135488
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GnomAD4 exome AF: 0.000320 AC: 467AN: 1460746Hom.: 0 Cov.: 31 AF XY: 0.000288 AC XY: 209AN XY: 726736
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 31, 2024 | The RAD50 c.1336A>G (p.Lys446Glu) variant has been reported in the published literature in individuals with breast cancer (PMID: 24894818 (2014)) and ovarian cancer (PMID: 30441849 (2018)). This variant has also been reported in an unaffected individual who also carried a gross exonic deletion in the RAD51C gene (PMID: 28709830 (2017)). In a large breast cancer association study, this variant was found in individuals with breast cancer cases as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.0014 (36/26090 chromosomes (Genome Aggregation Database, 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2022 | Observed in individuals with breast cancer and in an unaffected female with a family history of ovarian and other cancers who also carried a pathogenic variant in RAD51C (Haiman 2013, Damiola 2014, Lu 2015, Schoolmeester 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards 2015); This variant is associated with the following publications: (PMID: 24894818, 26689913, 26787654, 28709830, 23555315) - |
Nijmegen breakage syndrome-like disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 15, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 446 of the RAD50 protein (p.Lys446Glu). This variant is present in population databases (rs149217423, gnomAD 0.05%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 24894818, 26689913, 30441849). ClinVar contains an entry for this variant (Variation ID: 140939). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2020 | 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2018 | Variant summary: RAD50 c.1336A>G (p.Lys446Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 276328 control chromosomes. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. The variant, c.1336A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for pathogenicity (Damiola_2014, Haiman_2013, Lu_2015, Schoolmeester_2017, Young_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (RAD51C 5'UTR through exon 5 deletion; Schoolmeester_2017), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
.;.;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N;N
REVEL
Uncertain
Sift
Uncertain
.;.;.;D;T
Sift4G
Benign
.;.;.;T;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.81
MVP
0.58
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at