Submissions for variant NM_000314.8(PTEN):c.80-1_80del

dbSNP: rs1554893747

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595358	SCV000700901	pathogenic	not provided	2015-07-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000988412	SCV001138123	pathogenic	PTEN hamartoma tumor syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260300	SCV001437222	uncertain significance	not specified	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.80-1_80delGA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Though computational tools were not able to predict an impact on splicing for this variant, it is still possible that the variant can abolish the canonical splice acceptor site. However, this has yet to be confirmed by functional studies. The variant was absent in 250762 control chromosomes (gnomAD). To our knowledge, no occurrence of c.80-1_80delGA in individuals affected with Cowden Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, other variants affecting the same splice site were reported in affected individuals (in HGMD and ClinVar). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
MGZ Medical Genetics Center	RCV002289888	SCV002580291	likely pathogenic	Cowden syndrome 1	2021-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420566	SCV002678687	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The c.80-1_80delGA pathogenic mutation spans the canonical acceptor site of coding exon 2 in the PTEN gene. This variant results from a deletion of 2 nucleotides at positions c.80-1 to c.80. This alteration is located within a predicted U12-type intron for which available in silico tools are not reliable as determined by the ClinGen PTEN variant curation expert panel (Mester JL et al. Hum Mutat. 2018 11;39:1581-1592). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000988412	SCV004177026	pathogenic	PTEN hamartoma tumor syndrome	2023-09-13	criteria provided, single submitter	clinical testing	A PTEN c.80-2_80-1delAG variant was identified at near heterozygous allelic fraction and, to our knowledge, it has not been reported in the medical literature. This variant has been classified in the ClinVar database (described as c.80-1_80del) with conflicting interpretations of pathogenicity by five submitters (ClinVar ID: 496970). PTEN c.80-2_80-1delAG is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs within the canonical splice acceptor site, which is predicted to result in loss of function of the gene product. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen PTEN Expert Panel Specification Registry, the PTEN c.80-2_80-1delAG variant is classified as pathogenic.
Invitae	RCV000988412	SCV004385789	likely pathogenic	PTEN hamartoma tumor syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 2 (c.80-1_80del) of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 496970). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.