Submissions for variant NM_000314.8(PTEN):c.838A>G (p.Ile280Val)

dbSNP: rs1474354667

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000549116	SCV002576575	uncertain significance	PTEN hamartoma tumor syndrome	2020-10-20	reviewed by expert panel	curation	PTEN c.838A>G (p.Ile280Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). 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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29706350, PMID 29785012)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549116	SCV000645628	uncertain significance	PTEN hamartoma tumor syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 280 of the PTEN protein (p.Ile280Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 468719). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350, 29785012). 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.
Ambry Genetics	RCV000569322	SCV000666985	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	The p.I280V variant (also known as c.838A>G), located in coding exon 8 of the PTEN gene, results from an A to G substitution at nucleotide position 838. The isoleucine at codon 280 is replaced by valine, 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 functionally intermediate (Mighell TL et al. Am J Hum Genet. 2018 05;102:943-955). This variant demonstrated wildtype-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet. 2018 06;50:874-882). This variant has been detected in multiple individuals with no reported features of PTEN-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678741	SCV000804913	likely benign	Cowden syndrome	2018-07-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569322	SCV001352573	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 280 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 shown that this variant results is cellular lipid phosphatase activity and protein abundance similar to wild-type (PMID: 29706350, 29785012). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has been identified in 1/249780 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237915	SCV002009262	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569322	SCV002528271	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235282	SCV003934446	uncertain significance	not specified	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.838A>G (p.Ile280Val) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain (IPR014020) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249780 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.838A>G has been reported in the literature in one family with breast cancer, with no evidence of segregation with disease (Tsai_2019). Functional evidence using a humanized yeast model shows the variant has wild-type like lipid phosphatase activity (Mighell_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29706350, 30374176). Seven ClinVar submitters, including one expert panel (ClinGen PTEN curation panel), have assessed the variant since 2014: six classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003237915	SCV004030618	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate wildtype-like lipid phosphatase activity and protein stability (Matreyek et al., 2018; Mighell et al., 2018); Observed in an individual with breast cancer with a reported extended family history of breast and endometrial cancer, goiter, and larger head size; however, segregation was not confirmed (Tsai et al., 2019); This variant is associated with the following publications: (PMID: 18626510, 29785012, 29706350, 27535533, 30374176)
Baylor Genetics	RCV003470760	SCV004206687	uncertain significance	Glioma susceptibility 2	2024-03-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492094	SCV004239986	uncertain significance	Breast and/or ovarian cancer	2022-07-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000549116	SCV004838581	uncertain significance	PTEN hamartoma tumor syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 280 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 shown that this variant results is cellular lipid phosphatase activity and protein abundance similar to wild-type (PMID: 29706350, 29785012). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has been identified in 1/249780 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000569322	SCV005402724	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 GRCh37:10:89720687:A>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BS1_Supporting'] and an overall classification of Likely Benign