ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.634+5G>A (rs138336847)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000285177 SCV000329758 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing The c.634+5G>A splice site variant in the PTEN gene has previously been reported in association with PTEN-hamartoma tumor syndrome (PHTS) (Parisi et al., 2001; Lachlan et al., 2007; Boccone et al., 2008). This variant was assumed to be de novo in at least two individuals (Lachlan et al., 2007; Boccone et al., 2008). The c.634+5G>A variant is expected to destroy the splice donor site in intron 6, and to cause abnormal gene splicing. In addition, a different substitution at the same nucleotide (c.634+5G>T) has previously been reported in association with PHTS (Marsh et al., 1999). We consider c.634+5G>A to be pathogenic.
Ambry Genetics RCV000491116 SCV000580073 pathogenic Hereditary cancer-predisposing syndrome 2016-09-19 criteria provided, single submitter clinical testing The c.634+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 6 in the PTEN gene. This mutation has been identified in multiple individuals with PTEN hamartoma tumor syndrome (PTHS) (Parisi MA et al. J. Med. Genet., 2001 Jan;38:52-8; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Kersseboom R et al. Clin. Genet., 2012 Jun;81:555-62; Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60). In one study, RNA analysis indicated that this mutation causes out-of-frame skipping of coding exon 6, leading to a premature stop codon (Boccone L et al. Am. J. Med. Genet. A, 2008 Jan;146A:257-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000703228 SCV000832120 pathogenic PTEN hamartoma tumor syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Bannayan Riley Ruvalcaba syndrome and Cowden syndrome (PMID: 17526800, 18080326). This variant is also known as IVS6+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 280031). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in skipping of PTEN exon 6 (PMID: 18080326). For these reasons, this variant has been classified as Pathogenic.

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