Submissions for variant NM_000314.8(PTEN):c.1066A>G (p.Asn356Asp)

dbSNP: rs587782345

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131284	SCV000186253	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-09	criteria provided, single submitter	clinical testing	The p.N356D variant (also known as c.1066A>G), located in coding exon 9 of the PTEN gene, results from an A to G substitution at nucleotide position 1066. The asparagine at codon 356 is replaced by aspartic acid, an amino acid with highly similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was wild type-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). Based on internal structural analysis, this alteration is in a solvent exposed, unstructured portion of the protein, is associated with low free energy change, and is not known to be involved in any interactions; therefore, the change from asparagine to aspartic acid (a change from neutral to negative) is not expected to have a significant functional effect (Dosztányi Z et al. J. Mol. Biol., 2005 Apr;347:827-39; Li G et al. Cancer Cell, 2014 Apr;25:455-68). This alteration has been reported as a pathogenic mutation in multiple publications from the same research group (Mester JL et al. Eur. J. Hum. Genet. 2011 Jul;19(7):763-8; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2063-71; Tan MH et al. Am. J. Hum. Genet. 2011 Jan;88(1):42-56; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463640	SCV000541613	uncertain significance	PTEN hamartoma tumor syndrome	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 356 of the PTEN protein (p.Asn356Asp). 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 PTEN hamartoma tumor syndrome (PHTS) (PMID: 21194675). ClinVar contains an entry for this variant (Variation ID: 142263). 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 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 32350270). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131284	SCV000691140	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818323	SCV002070087	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818323	SCV002600820	uncertain significance	not specified	2022-10-30	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.1066A>G (p.Asn356Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1066A>G has been reported in the literature multiple times from the same group, indicating it occurs in at least one individual affected with Cowden Syndrome (Mester_2011, Tan_2011, Ngeow_2011, Nizialek_2015). These data do not allow any conclusion about variant significance. At least one publication using a yeast assay to evaluate the impact of the variant on lipid phosphatase activity showed the variant had "wild-type like activity" (Michell_2018). Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477549	SCV004219123	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with PTEN hamartoma syndrome, including Cowden and Cowden-like syndrome (PMIDs: 25669429 (2015), 21343951 (2011), 21194675 (2011), 21956414 (2011)). One experimental study reports the variant has little to no impact on PTEN protein function (PMID: 29706350 (2018)), however further evidence is needed to understand the variant's global impact on proper PTEN function. The frequency of this variant in the general population, 0.0000041 (1/245272 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.
All of Us Research Program, National Institutes of Health	RCV000463640	SCV004838602	uncertain significance	PTEN hamartoma tumor syndrome	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 356 of the PTEN protein. Functional studies have reported this variant was neutral in lipid phosphatase assays (PMID: 29706350, 32350270). This variant has been reported in an individuals affected with Cowden syndrome in the literature (PMID: 21194675). This variant has been identified in 1/245272 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.
Baylor Genetics	RCV004567128	SCV005052562	uncertain significance	Glioma susceptibility 2	2024-02-05	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000131284	SCV005402558	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 GRCh38:10:87965326:A>G was assigned evidence codes ['BS3_Supporting', 'BP4'] and an overall classification of Likely benign