Submissions for variant NM_005732.4(RAD50):c.129+5G>A

gnomAD frequency: 0.00001  dbSNP: rs587781409

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129269	SCV000184029	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The c.129+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 1 in the RAD50 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000129269	SCV000261012	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the RAD50 gene. It does not directly change the encoded amino acid sequence of the RAD50 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587781409, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 140976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780662	SCV000918121	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.129+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 1614082 control chromosomes, predominantly at a frequency of 6.8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.129+5G>A has been reported in the literature in at-least one individual affected with breast and/or ovarian cancer and the authors of this report classified the variant as VUS (example: de Oliveira_2022). The following publication has been ascertained in the context of this evaluation (PMID: 35534704). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 140976). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV002257454	SCV002538451	uncertain significance	Nijmegen breakage syndrome-like disorder	2022-03-18	criteria provided, single submitter	curation
Baylor Genetics	RCV002257454	SCV004207338	uncertain significance	Nijmegen breakage syndrome-like disorder	2023-12-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477539	SCV004219277	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000055 (7/128412 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on RAD50 mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003945143	SCV004765053	likely benign	RAD50-related disorder	2019-11-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).