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

Total submissions: 3

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	Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae	RCV000703228	SCV000832120	pathogenic	PTEN hamartoma tumor syndrome	2018-10-19	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.