ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2607+5G>A (rs143862573)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413101 SCV000490771 likely pathogenic not provided 2016-03-22 criteria provided, single submitter clinical testing The c.2607+5G>A variant in the RET gene has been previously reported in an individual with long segment Hirschsprung disease (Auricchio et al., 1999). This variant is predicted to damage or destroy the natural splice donor site of intron 14, and is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.2607+5G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret c.2607+5G>A as a likely pathogenic variant, which may be related to abdominal pain and bloody stools. However, the possibility it may be a rare benign variant cannot be excluded. This variant has been seen to be maternally inherited.
Counsyl RCV000663278 SCV000786515 uncertain significance Multiple endocrine neoplasia, type 2a 2018-05-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016044 SCV001176955 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001244630 SCV001417864 uncertain significance Multiple endocrine neoplasia, type 2 2019-08-02 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the RET gene. It does not directly change the encoded amino acid sequence of the RET protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs143862573, ExAC 0.009%). This variant has been reported in an individual affected with Hirschsprung disease (PMID: 10090908). ClinVar contains an entry for this variant (Variation ID: 372491). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.