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

gnomAD frequency: 0.00001  dbSNP: rs143862573

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413101	SCV000490771	uncertain significance	not provided	2023-02-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); While in silico analysis supports that this variant does not alter splicing, a published mini-gene assay suggests an altered splice effect (Jiang et al., 2021); This variant is associated with the following publications: (PMID: 25525159, 33433679, 10090908, 35875156)
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	2021-07-15	criteria provided, single submitter	clinical testing	The c.2607+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 14 in the RET gene. This nucleotide position is well conserved in available vertebrate species. This alteration was reported in an individual with sporadic Hirschprung's disease (Auricchio A et al. Am. J. Hum. Genet., 1999 Apr;64:1216-21). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001244630	SCV001417864	uncertain significance	Multiple endocrine neoplasia, type 2	2023-10-22	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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs143862573, gnomAD 0.003%). This variant has been observed in individual(s) with intestinal aganglionosis (PMID: 10090908, 33433679). ClinVar contains an entry for this variant (Variation ID: 372491). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 33433679). 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	RCV002469143	SCV002766431	uncertain significance	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: RET c.2607+5G>A alters a non-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: four predict the variant weakens a 5' donor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing (Jiang_2021), however the protein level effect (i.e. residual function) of the variant cannot be predicted based on these data. The variant allele was found at a frequency of 4e-06 in 248788 control chromosomes (i.e. 1 carrier in the gnomAD v2.1 exomes dataset). The variant, c.2607+5G>A has been reported in the literature in an Italian individual affected with sporadic Hirschsprung Disease (HD) (Auricchio_1999). The variant was also reported in a child (Chinese) affected with total intestinal aganglionosis, who inherited the variant from the unaffected father (Jiang_2021). The authors proposed the presence of a risk haplotype contributing to the disease by "enhancing" the penetrance of this RET variant in the affected proband. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic risk factor for Hirschsprung Disease.
Myriad Genetics, Inc.	RCV000663278	SCV004018057	uncertain significance	Multiple endocrine neoplasia, type 2a	2023-04-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.