Submissions for variant NM_000314.8(PTEN):c.966A>G (p.Lys322=)

dbSNP: rs786201392

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163533	SCV000214091	likely benign	Hereditary cancer-predisposing syndrome	2017-08-28	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	RCV000555714	SCV000645637	likely benign	PTEN hamartoma tumor syndrome	2024-09-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163533	SCV000903643	likely benign	Hereditary cancer-predisposing syndrome	2018-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001711438	SCV001939482	likely benign	not provided	2019-06-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000555714	SCV004838594	likely benign	PTEN hamartoma tumor syndrome	2023-06-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354098	SCV001548628	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PTEN p.Lys322= variant was identified in the literature in a 20 year old female patient with Cowden syndrome however the frequency of this variant in an affected population was not provided (Gammon 2013). The variant was also identified in dbSNP (ID: rs786201392) as “With Likely benign allele” and ClinVar (2x as likely benign by Ambry genetics, Invitae).The variant was not identified in LOVD 3.0. 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 c.966A>G variant is identified in an affected patient with Cowden Syndrome co-occurring with a pathogenic PTEN variant (c.967delA, p.Asn323Metfs*21) (Gammon 2013). In addition the variant was identified in our laboratory in an individual with breast cancer, with a co-occurring pathogenic ATM variant (c.6916_6917del, p.Leu2307Cys*65), increasing the likelihood that the p.Glu13Lys variant does not have clinical significance. The p.Lys322= 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 outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
PreventionGenetics, part of Exact Sciences	RCV004539529	SCV004794933	likely benign	PTEN-related disorder	2019-04-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).