rs146370443
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_005732.4(RAD50):âc.1094G>Aâ(p.Arg365Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,613,590 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R365G) has been classified as Uncertain significance.
Frequency
Genomes: đ 0.00028 ( 0 hom., cov: 32)
Exomes đ: 0.00034 ( 1 hom. )
Consequence
RAD50
NM_005732.4 missense
NM_005732.4 missense
Scores
2
10
Clinical Significance
Conservation
PhyloP100: 1.06
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 -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.018426448).
BP6
Variant 5-132588729-G-A is Benign according to our data. Variant chr5-132588729-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127990.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=9, Benign=1, Likely_benign=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RAD50 | NM_005732.4 | c.1094G>A | p.Arg365Gln | missense_variant | 8/25 | ENST00000378823.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RAD50 | ENST00000378823.8 | c.1094G>A | p.Arg365Gln | missense_variant | 8/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes 0.000283 AC: 43AN: 151772Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000458 AC: 115AN: 251162Hom.: 0 AF XY: 0.000464 AC XY: 63AN XY: 135728
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GnomAD4 exome AF: 0.000337 AC: 492AN: 1461700Hom.: 1 Cov.: 32 AF XY: 0.000351 AC XY: 255AN XY: 727152
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GnomAD4 genome 0.000283 AC: 43AN: 151890Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74210
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 27, 2022 | The frequency of this variant in the general population, 0.0011 (38/33046 chromosomes in the 'Other non-Finnish European' subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals or families with breast/ovarian cancer (PMIDs: 32854451 (2020), 31159747 (2019), 30306255 (2018), 28550065 (2017), 24894818 (2014)), ovarian cancer alone (PMIDs: 30441849 (2018), 26689913 (2015)), and colorectal cancer (PMID: 33563768 (2022)). 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 benign. 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 | May 17, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and ovarian cancer (Lu 2015, Fanale 2020); This variant is associated with the following publications: (PMID: 31159747, 32854451, 30441849, 26689913) - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD50 p.Arg365Gln variant was identified in 5 of 10694 proband chromosomes (frequency: 0.000468) from individuals or families with breast and ovarian cancer and was not identified in 1121 control chromosomes from healthy individuals (Damiola_2014_24894818; Lu_2015_PMID: 26689913). The variant was also identified in dbSNP (ID: rs146370443), ClinVar (conflicting interpretations of pathogenicity: one likely benign submission by Ambry Genetics and four VUS submissions by GeneDx, Invitae, Fulgent Genetics and GeneKor MSA; associated conditions are Nijmegen breakage syndrome-like disorder and Hereditary cancer-predisposing syndrome. The variant was identified in control databases in 122 of 282506 chromosomes at a frequency of 0.000432 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was not identified in the Cosmic and LOVD 3.0 databases. The variant was observed in the following populations: European (non-Finnish) in 79 of 128920 chromosomes (freq: 0.000613), East Asian in 12 of 19952 chromosomes (freq: 0.000601), South Asian in 16 of 30592 chromosomes (freq: 0.000523), Other in 3 of 7210 chromosomes (freq: 0.000416), Latino in 8 of 35398 chromosomes (freq: 0.000226), European (Finnish) in 4 of 25110 chromosomes (freq: 0.000159), while the variant was not observed in the African, and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg365 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2019 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). 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. - |
RAD50-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2023 | The RAD50 c.1094G>A variant is predicted to result in the amino acid substitution p.Arg365Gln. This variant has been reported as a variant of uncertain significance in patients tested using a panel of genes for hereditary cancer syndrome (Table S5, Tsaousis et al. 2019. PubMed ID 3115974), as well as in patients with breast or ovarian cancer (Table S9, Bonache et al. 2018. PubMed ID: 30306255; Damiola et al. 2014. PubMed ID 24894818; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S12, Lu et al. 2015. PubMed ID 26689913; Table 4, Fanale et al. 2020. PubMed ID 32854451). It has also been reported in a metastatic liver biopsy specimen (Table S2, Parachoniak et al. 2017. PubMed ID: 28550065). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131924421-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127990/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 06, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"Íž PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Nijmegen breakage syndrome-like disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2023 | Variant summary: RAD50 c.1094G>A (p.Arg365Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251162 control chromosomes. The observed variant frequency is approximately 7.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. c.1094G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome as well as other types of cancer (example, Lu_2015, Bonache_2018, Damiola_2014, Koczkowska_2018, Parachoniak_2017, Tsaousis_2019, Young_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, six classified the variant as a VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Familial cancer of breast;C2751318:Nijmegen breakage syndrome-like disorder Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 06-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
Polyphen
0.013
.;.;.;B;.
Vest4
0.21
MVP
0.41
ClinPred
T
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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