ClinVar Miner

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

dbSNP: rs1474354667
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Total submissions: 12
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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)
Invitae RCV000549116 SCV000645628 uncertain significance PTEN hamartoma tumor syndrome 2023-09-06 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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function. 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.

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