Submissions for variant NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln)

gnomAD frequency: 0.00003  dbSNP: rs375709098

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000205690	SCV000886865	likely benign	PTEN hamartoma tumor syndrome	2023-06-14	reviewed by expert panel	curation	NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) variant 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). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350). BP4: REVEL score < 0.5 (score=0.497). 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. Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign).
Ambry Genetics	RCV000132539	SCV000187636	likely benign	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000513025	SCV000222169	uncertain significance	not provided	2018-08-07	criteria provided, single submitter	clinical testing	This variant is denoted PTEN c.1061C>A at the cDNA level, p.Pro354Gln (P354Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). Mester et al. (2011) reported this variant occurring in two related individuals with features of Cowden syndrome, however neither met International Cowden Syndrome Consortium diagnostic criteria. Pilarski et al. (2011) reported an additional patient with this variant identified through clinical PTEN testing. Yurgelun et al. (2015) identified this variant in an individual undergoing multi-gene cancer panel testing based on a history of a Lynch syndrome-related cancer and/or polyps; this particular individual was also found to harbor a pathogenic MSH2 variant. Lastly, this variant was observed in an individual with neuroblastoma and in an individual with a personal and family history of breast cancer (Zhang 2015, Caminsky 2016). PTEN Pro354Gln was observed at an allele frequency of 0.016% (19/122,896) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PTEN Pro354Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000205690	SCV000260548	benign	PTEN hamartoma tumor syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210607	SCV000263012	uncertain significance	Inborn genetic diseases	2015-10-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000409006	SCV000488776	uncertain significance	Cowden syndrome 1	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513025	SCV000608561	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000201314	SCV000696524	likely benign	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.1061C>A (p.Pro354Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 244884 control chromosomes. The observed variant frequency is approximately 13.067 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.1061C>A has been reported in the literature in sequencing studies of individuals affected with gliomas (Caldera_2011, tumor sequencing of large cell carcinomas (Karlsson_2015), PTEN Hamartoma Tumour Syndrome (Mester_2011), PTEN clinical testing cohort (Pilarski_2011), individuals meeting relaxed Cowden syndrome criteria (Tan_2011), LS clinical testing cohort (Yurgelun_2015), an unpublished case report of an individual undergoing diagnostic exome sequencing with an unrelated phenotype who's unaffected mother and brother carried the variant of interest (Tsang_2015) and as a variant that was excluded from a case control study analysis due to low penetrance (Couch_2018). At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.2047G>A, p.Gly683Arg), providing supporting evidence for a benign role (Yurgelun_2015). Additionally, the variant was reported to have wild-type range of function via a high throughput phosphatase assay (Mighell_2018). The following publications have been ascertained in the context of this evaluation (PMID: 21869887, 28418444, 26124082, 21343951, 21659347, 21194675, 25980754, 29706350). ClinVar contains an entry for this variant (Variation ID: 143020), with a likely benign classification from the Clingen PTEN Variant Curation Expert Panel. Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000513025	SCV000704628	uncertain significance	not provided	2016-12-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000201314	SCV000711737	uncertain significance	not specified	2019-01-30	criteria provided, single submitter	clinical testing	The p.Pro354Gln variant in PTEN has been reported in 6 individuals with a clinical diagnosis or features of PTEN hamartoma tumor syndrome and segregated with disease in at least 1 affected relative (Mester 2011, Pilarski 2011, Tan 2011, Nizialek 2015, Zhang 2015, Caminsky 2016). This variant was also reported in 1 individual with features of Lynch syndrome, who also carried a pathogenic variant in MSH2 (Yurgelun 2015). Other clinical laboratories have reported this variant in ClinVar (Variation ID: 143020). It has also been identified in 21/270810 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro354Gln variant is uncertain. the ACMG/AMP criteria applied: PS4_Moderate, BP5.
PreventionGenetics, part of Exact Sciences	RCV003891673	SCV000806058	uncertain significance	PTEN-related condition	2024-01-16	criteria provided, single submitter	clinical testing	The PTEN c.1061C>A variant is predicted to result in the amino acid substitution p.Pro354Gln. This variant has been documented in Cowden syndrome patients and at least one of them had breast cancer (Table S2, Tan et al. 2011. PubMed ID: 21194675; Mester et al. 2011. PubMed ID: 21343951; Table S4, Nizialek et al. 2015. PubMed ID: 25669429), in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMedID: 25980754), in an individual with breast or ovarian cancer (Caminsky et al. 2016. PubMed ID: 26898890), in an individual with pancreatic ductal adenocarcinoma (Supplementary Table 3, Cremin et al. 2020. PubMed ID: 32255556), and in an individual with melanoma (Li et al. 2019. PubMed ID: 31567591). This variant has also been documented in patient with autism spectrum disorder (Patient 01-021 in Supplemental Table 2, Busch et al. 2019. PubMed ID: 31594918). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has interpretations ranging from benign to uncertain in ClinVar, with an expert curation panel interpreting it as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/143020). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513025	SCV000889800	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast cancer (PMID: 21343951 (2011)), suspected Lynch syndrome (PMID: 25980754 (2015)), melanoma (PMID: 31567591 (2020)), hamartoma tumor syndrome (PMID: 35931053 (2022)), and in individuals with features of Cowden syndrome (PMID: 25669429 (2015)). In a large-scale breast cancer association study, this variant was observed in breast cancer cases as well as study controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)). In addition, multiple experimental studies have shown this variant has a neutral effect on PTEN lipid phosphatase activity and protein abundance (PMIDs: 29706350 (2018), 29785012 (2018), and 32350270 (2020)). The frequency of this variant in the general population, 0.00015 (19/125384 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000132539	SCV000910731	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 354 of the PTEN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the variant protein to be functional in a lipid phosphatase assay with a fitness score resembling those of synonymous variants (PMID: 29706350) and in protein stability/abundance assay (PMID: 29785012). This variant has been reported in individuals suspected of having Cowden syndrome (PMID: 21659347, 25669429) and Lynch syndrome (PMID: 25980754), as well as in individuals affected with breast/ovarian cancer (PMID: 21343951, 26898890), neuroblastoma (PMID: 26580448), melanoma (PMID: 31006514), and lung cancer (PMID: 26124082). This variant occurs at an elevated frequency in the general population and has been identified in 21/276260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000132539	SCV002528214	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000201314	SCV002760487	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492515	SCV002796389	uncertain significance	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; Glioma susceptibility 2; Cowden syndrome 1	2022-01-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409006	SCV004019901	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	RCV003492631	SCV004239978	uncertain significance	Breast and/or ovarian cancer	2023-05-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201314	SCV000692023	uncertain significance	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357175	SCV001552553	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PTEN p.Pro354Gln variant was identified in 8 of 20700 proband chromosomes (frequency: 0.0004) from individuals or families with Cowden syndrome, Neuroblastoma, lynch syndrome, breast or ovarian cancer and was not identified in 222 control chromosomes from healthy individuals (Tan 2011, Zhang 2015, Pilarski 2011, Mester 2011, Yurgelun 2015, Nizialek 2015, Caminsky 2016). The variant was also identified in dbSNP (ID: rs375709098) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl and 5 clinical laboratories), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 21 of 270810 chromosomes at a frequency of 0.0001 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 2 of 23476 chromosomes (freq: 0.0001), European in 19 of 122896 chromosomes (freq: 0.0002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro354 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000409006	SCV004174078	uncertain significance	Cowden syndrome 1		no assertion criteria provided	clinical testing