Submissions for variant NM_000314.8(PTEN):c.75G>A (p.Leu25=)

gnomAD frequency: 0.00001  dbSNP: rs786201506

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000553143	SCV000840466	likely benign	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(PTEN):c.75G>A (p.Leu25=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS3: Synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor) BP7: Variant is synonymous and no splicing impact is predicted. PM2_P: Absent in gnomAD. Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong, 1 benign supporting and 1 pathogenic supporting codes get -4 + (-1) + 1 points; total is – 4 (likely benign).
Ambry Genetics	RCV000163772	SCV000214353	likely benign	Hereditary cancer-predisposing syndrome	2014-10-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553143	SCV000645620	likely benign	PTEN hamartoma tumor syndrome	2024-10-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163772	SCV000686302	likely benign	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001753554	SCV002007349	uncertain significance	not provided	2019-10-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30311380)
All of Us Research Program, National Institutes of Health	RCV000553143	SCV004838533	likely benign	PTEN hamartoma tumor syndrome	2023-09-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358393	SCV001554111	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PTEN p.Leu25= variant was not identified in the literature nor was it identified in the LOVD 3.0 databases. The variant was identified in dbSNP (rs786201506) as “with likely benign, uncertain significance allele” and ClinVar (classfied as likely benign by Invitae, Color and Ambry Genetics and uncertain significance by ClinGen PTEN variant panel). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Leu25= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.