Submissions for variant NM_000314.8(PTEN):c.132C>T (p.Gly44=)

gnomAD frequency: 0.00168  dbSNP: rs150651961

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000123045	SCV000840470	likely benign	PTEN hamartoma tumor syndrome	2016-11-09	reviewed by expert panel	curation	PTEN c.132C>T (p.G44=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Allele frequency of 0.167 (1.67%, 463/276,792 alleles) in the gnomAD cohort. (PMID 27535533) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000212700.3) BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000212700.3) BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted.
Eurofins Ntd Llc (ga)	RCV000078606	SCV000110462	benign	not specified	2013-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV000123045	SCV000166340	benign	PTEN hamartoma tumor syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162387	SCV000212700	benign	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000123045	SCV000365736	likely benign	PTEN hamartoma tumor syndrome	2018-06-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000078606	SCV000604970	benign	not specified	2019-02-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512721	SCV000608560	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PTEN: BS1
Color Diagnostics, LLC DBA Color Health	RCV000162387	SCV000686277	likely benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000512721	SCV000696530	benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: The c.132C>T variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 3/5 programs in Alamut predict that this variant may create a novel 5' splicing donnor site. ESE finder predicts that this variant may affect ESE site of SRp55. However, these predictions are not confirmed by experimental studies. This variant is found in 190/121096 control chromosomes (1 homozygote) at a frequency of 0.001569. These alleles are unlikely from the PTEN pseudogene based on the sequence homology analysis and homozygous occurrences. This frequency is about 282 times of maximal expected frequency of a pathogenic allele (0.0000056), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as benign/likely benign. Taken together, this variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000078606	SCV000806055	benign	not specified	2016-05-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078606	SCV000888588	benign	not specified	2022-05-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000512721	SCV001754035	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000512721	SCV002009267	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798276	SCV002042717	likely benign	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078606	SCV002072203	benign	not specified	2021-04-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162387	SCV002528220	benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000078606	SCV002549952	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315602	SCV004017208	benign	Cowden syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078606	SCV000692003	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162387	SCV000788197	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357961	SCV001553575	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PTEN p.Gly44= variant was identified in 3 of 2724 proband chromosomes (frequency: 0.001) from individuals or families with prostate, breast cancer or Cowden syndrome and was not identified in 322 control chromosomes from healthy individuals (Bar-Shira 2006, Kurose 2002, Nizialek 2015). The variant was also identified in large population study by Momozawa (2018) in 6 of 14102 female chromosomes (frequency: 0.0004), and 4 in 22482 female control chromosomes (frequency: 0.0002) and 7 in 24980 male control chromosomes (frequency: 0.0003). The variant was also identified in dbSNP (ID: rs150651961) as "With other allele", ClinVar (classified as benign by Invitae, ARUP and four other submitters; as likely benign by eight submitters), LOVD 3.0 (7x as benign or likely benign). The variant was identified in control databases in 463 of 276792 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24028 chromosomes (freq: 0.0001), Other in 16 of 6452 chromosomes (freq: 0.003), Latino in 5 of 34378 chromosomes (freq: 0.0002), European in 319 of 126434 chromosomes (freq: 0.003), Ashkenazi Jewish in 33 of 10142 chromosomes (freq: 0.003), East Asian in 3 of 18856 chromosomes (freq: 0.0002), Finnish in 84 of 25724 chromosomes (freq: 0.003); it was not observed in the and South Asian populations. The p.Gly44= 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 2 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000512721	SCV001740144	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078606	SCV001918907	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078606	SCV001958212	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000512721	SCV001972403	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000078606	SCV002035206	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000512721	SCV002036346	likely benign	not provided		no assertion criteria provided	clinical testing