Submissions for variant NM_000314.8(PTEN):c.579G>A (p.Leu193=)

gnomAD frequency: 0.00010  dbSNP: rs568851024

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000123049	SCV001244238	likely benign	PTEN hamartoma tumor syndrome	2019-11-22	reviewed by expert panel	curation	PTEN c.579G>A (p.Leu193=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS1: Allele frequency of 0.00125 (0.125%, 13/10,360 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123049	SCV000166344	benign	PTEN hamartoma tumor syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162705	SCV000213165	likely benign	Hereditary cancer-predisposing syndrome	2014-09-18	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.
Illumina Laboratory Services, Illumina	RCV000123049	SCV000365739	benign	PTEN hamartoma tumor syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000437368	SCV000514312	benign	not specified	2015-06-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000437368	SCV000596621	likely benign	not specified	2016-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162705	SCV000686293	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437368	SCV000696536	benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000663101	SCV000786211	likely benign	Cowden syndrome 1	2018-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001312160	SCV001502625	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	PTEN: BP4
Sema4, Sema4	RCV000162705	SCV002528249	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663101	SCV004019905	benign	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162705	SCV004228134	benign	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492538	SCV004239983	likely benign	Breast and/or ovarian cancer	2022-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123049	SCV004838564	likely benign	PTEN hamartoma tumor syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357128	SCV001552488	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PTEN p.Leu193= variant was identified in 2 of 2194 proband chromosomes (frequency: 0.001) from individuals or families with Cowden syndrome (Nizialek 2015, Sarquis 2006). The variant was also identified in dbSNP (ID: rs568851024) as With other allele, ClinVar (classified as benign by Invitae, GeneDx; as likely benign by Ambry Genetics, Color Genomics; as uncertain significance by Integrated Genetics), Clinvitae, LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 27 of 276780 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 5 of 34416 chromosomes (freq: 0.0002), European in 5 of 126450 chromosomes (freq: 0.00004), Ashkenazi Jewish in 13 of 10142 chromosomes (freq: 0.001), and South Asian in 2 of 30762 chromosomes (freq: 0.0001), while the variant was not observed in the African, East Asian, Finnish, populations. The p.Leu193= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004734662	SCV005351288	likely benign	PTEN-related disorder	2019-06-12	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).