ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1245+1G>A (rs1561639636)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneKor MSA RCV000708624 SCV000821771 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change occurs 1 nucleotides after exon 8 of the RAD50 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572). Also, donor and acceptor splice site variants as usual lead to a loss of protein function (PMID: 16199547). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747).
Ambry Genetics RCV001010527 SCV001170743 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-02 criteria provided, single submitter clinical testing The c.1245+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the RAD50 gene. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This nucleotide position is highly conserved in available vertebrate species. The ESE splice prediction software predicts that this alteration will abolish the native splice donor site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to weaken the native splice donor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV001010527 SCV001232882 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the RAD50 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported individual(s) referred for hereditary cancer genetic testing (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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