ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.634+1G>A

dbSNP: rs1114167622
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001025158 SCV001187293 pathogenic Hereditary cancer-predisposing syndrome 2023-08-07 criteria provided, single submitter clinical testing The c.634+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the PTEN gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (PHTS, Ambry internal data). Another alteration impacting the same donor site (c.634+5G>A) has been shown to have a similar impact on splicing in multiple individuals with PHTS (Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Kersseboom R et al. Clin. Genet., 2012 Jun;81:555-62, Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
GeneDx RCV001555914 SCV001777407 pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21194675, 23470840)

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