ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.635-1G>C (rs876661024)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000515885 SCV000579240 pathogenic Cowden syndrome 1 2017-05-26 no assertion criteria provided research
GeneDx RCV000221132 SCV000279240 pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing The c.635-1 G>C splice site variant in the PTEN gene has been previously reported in association with PTEN-related disorders (Marsh et al., 1999; Heald et al., 2010; Tan et al., 2011). This pathogenic variant destroys the canonical splice acceptor site in intron 6, and is expected to cause abnormal gene splicing. The c.635-1 G>C 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.
Invitae RCV000645031 SCV000766770 pathogenic PTEN hamartoma tumor syndrome 2018-03-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Bannayan-Riley-Ruvalcaba syndrome (PMID: 24379037) and to segregate with Cowden syndrome in one family (PMID: 16021145). It has also been reported in additional individuals affected with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (PMID: 10400993, 25669429, 23335809, 20600018, Invitae). This variant is also known as IVS6-1G>C and c.635G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 234446). Experimental studies have shown that this splice change results in utilization of cryptic splice sites creating unstable mRNA transcripts (PMID: 28677221). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.

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