Submissions for variant NM_000314.8(PTEN):c.1078A>G (p.Ser360Gly)

gnomAD frequency: 0.00002  dbSNP: rs587781273

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000205946	SCV000930119	likely benign	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(PTEN):c.1078A>G (p.Ser360Gly) 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). 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. BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00001171. BP4: REVEL score < 0.5 (score of this variant=0.441). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 2 benign supporting and 1 pathogenic supporting codes get (-1*2) + 1 points; total is –1 (likely benign).
Ambry Genetics	RCV000128915	SCV000172782	likely benign	Hereditary cancer-predisposing syndrome	2021-06-24	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	RCV000205946	SCV000259273	uncertain significance	PTEN hamartoma tumor syndrome	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 360 of the PTEN protein (p.Ser360Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with predominantly antibody disorders and breast and/or ovarian cancer (PMID: 32185379, 35264596). ClinVar contains an entry for this variant (Variation ID: 140777). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000410573	SCV000487947	uncertain significance	Cowden syndrome 1	2015-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000483006	SCV000570489	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: protein stability similar to wildtype (PMID: 29785012, 29706350); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32185379, 29706350, 29785012, 18626510, 33471991, 35264596, 34793697)
Mendelics	RCV000205946	SCV000838426	uncertain significance	PTEN hamartoma tumor syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483006	SCV001134770	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000073 (2/275738 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)) and in an individual with sepsis (PMID: 32185379 (2020)). A humanized, yeast-based functional study showed that this variant maintains the lipid phosphatase activity of the PTEN protein (PMID: 29706350 (2018)). Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000128915	SCV001354514	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 360 of the PTEN protein. A humanized, yeast-based functional study measuring lipid phosphatase activity demonstrated that the variant behaves similar wild-type PTEN in this assay (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000483006	SCV002049454	uncertain significance	not provided	2021-03-05	criteria provided, single submitter	clinical testing	The PTEN c.1078A>G; p.Ser360Gly variant (rs587781273), to our knowledge, is not reported in an individual with PTEN hamartoma tumor syndrome, but is reported in an individual with sepsis (Borghesi 2020). The variant is listed in the ClinVar database (Variation ID: 140777) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 360 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). References: Borghesi A et al. Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study. Clin Infect Dis. 2020 Mar 18;71(10):e614-23.
MGZ Medical Genetics Center	RCV000410573	SCV002581064	uncertain significance	Cowden syndrome 1	2022-07-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410573	SCV004019951	uncertain significance	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
CeGaT Center for Human Genetics Tuebingen	RCV000483006	SCV004701620	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PTEN: PP2, BS1:Supporting
All of Us Research Program, National Institutes of Health	RCV000205946	SCV004838605	uncertain significance	PTEN hamartoma tumor syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 360 of the PTEN protein. A humanized, yeast-based functional study measuring lipid phosphatase activity demonstrated that the variant behaves similar wild-type PTEN in this assay (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760386	SCV005373782	likely benign	Hereditary breast ovarian cancer syndrome	2024-07-08	criteria provided, single submitter	curation	According to the ClinGen ACMG PTEN v3.1.0 criteria we chose these criteria: PP2 (supporting pathogenic): Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease., BP4 (supporting benign): REVEL Score 0,441, BS1 (supporting benign): BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00001171.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000128915	SCV005402562	likely benign	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87965338:A>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BS1_Supporting'] and an overall classification of Likely benign