Submissions for variant NM_000314.8(PTEN):c.235G>A (p.Ala79Thr)

gnomAD frequency: 0.00011  dbSNP: rs202004587

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000123046	SCV000840467	likely benign	PTEN hamartoma tumor syndrome	2018-04-06	reviewed by expert panel	curation	PTEN c.235G>A (p.A79T) 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 0.0045 (0.45%, 9/1984 alleles) in the GME variome. (PMID 27428751) 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) SCV000222198.12) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123046	SCV000166341	benign	PTEN hamartoma tumor syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129085	SCV000183790	likely benign	Hereditary cancer-predisposing syndrome	2019-01-11	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.
GeneDx	RCV000034594	SCV000222198	likely benign	not provided	2020-09-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 26800850, 25980754, 25669429, 30728895, 12789288, 25527629, 10923032, 21659347, 21956414, 16171945, 23161105, 12372056, 21343951, 27720647, 27600092, 11297763, 24142049, 9619835, 21194675, 27477328, 28007035, 25925381, 22076652, 28873162, 29641532, 29371908, 29785012, 29706350, 31159747, 31209962, 31144778, 32350270, 32366478)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000123046	SCV000257666	uncertain significance	PTEN hamartoma tumor syndrome	2015-07-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000409443	SCV000487786	uncertain significance	Cowden syndrome 1	2015-11-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477056	SCV000611427	likely benign	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; Glioma susceptibility 2; Cowden syndrome 1	2022-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626250	SCV000746903	uncertain significance	Macrocephaly-autism syndrome	2017-12-18	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129085	SCV000822140	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000123046	SCV000838417	benign	PTEN hamartoma tumor syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034594	SCV000888591	likely benign	not provided	2023-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129085	SCV000902713	likely benign	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257777	SCV001434590	uncertain significance	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034594	SCV002009266	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129085	SCV002528230	likely benign	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001796959	SCV002760475	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409443	SCV004019904	likely benign	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492331	SCV004239980	uncertain significance	Breast and/or ovarian cancer	2022-09-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034594	SCV005330226	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PTEN: PP2, PP3, BS1
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034594	SCV000043462	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
AlTemaimi Lab, Faculty of Medicine, Kuwait University	RCV000409443	SCV000577862	pathogenic	Cowden syndrome 1	2017-05-19	no assertion criteria provided	clinical testing	CMT panel and gene duplication assays were negative and investigative exome sequencing was conducted. Clinical presentation is 80% match with Cowden Syndrome (exception unilateral pes cavus).
PreventionGenetics, part of Exact Sciences	RCV004528160	SCV000806056	likely benign	PTEN-related disorder	2019-12-24	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357785	SCV001553361	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PTEN p.Ala79Thr variant was identified in 10 of 47,988 proband chromosomes (frequency: 0.0002) from individuals or families with Bannayan-Riley Ruvalcaba syndrome, Cowden syndrome, PTEN hamartoma tumour syndrome, Lynch Syndrome, or ovarian or breast cancer and was present in 2 of 23,624 control chromosomes (frequency: 0.00008) from healthy individuals (Momozawa 2018, Figer 2002, Pilarski 2011, Tan 2011, Mester 2011, Dominguez-Valentin 2018, Nizialek 2015, Yurgelun 2015, Ngeow 2011). The variant was identified in dbSNP (rs202004587) as “with uncertain significance allele”, ClinVar (classified as likely benign by ClinGen PTEN Expert Panel in 2018, Ambry Genetics, GeneDx, and Color; as uncertain significance by Invitae, PreventionGenetics, Counsyl and 7 other submitters; and as pathogenic by Kuwait University) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 29 of 281,404 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 22 of 128,158 chromosomes (freq: 0.0002), South Asian in 5 of 30,560 chromosomes (freq: 0.0002), and Other in 1 of 7170 chromosomes (freq: 0.00004), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian or Finnish populations. However, this variant was also identified at an allele frequency of 0.005 in a Middle Eastern population, increasing the likelihood this could be a low frequency benign variant (Scott 2016). This variant has been identified in the homozygous state in one unaffected individual, decreasing the likelihood that this variant has clinical significance (PTEN expert panel internal data, per ClinVar entry dated April 6, 2018). The p.Ala79 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs 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.