ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.901G>A (p.Asp301Asn)

gnomAD frequency: 0.00001  dbSNP: rs758644748
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223261 SCV000278438 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing The p.D301N variant (also known as c.901G>A), located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 901. The aspartic acid at codon 301 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is located at an internal loop within the C2 domain of PTEN, which has been shown to facilitate the binding of PTEN to membranes; however, the precise function of its internal loop remains unknown (Torres J et al. J. Biol. Chem. 2003 Aug;278:30652-60). This alteration has been reported in 3 of 59 melanomas from 8 xeroderma pigmentosum (XP) patients, however authors also state that this alteration showed reduced AKT phosphorylation to a similar extent as wild-type PTEN, indicating that it did not alter this PTEN function (Wang Y et al. Proc. Natl. Acad. Sci. U.S.A. 2009 Apr;106:6279-84). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000699550 SCV000828265 uncertain significance PTEN hamartoma tumor syndrome 2023-08-01 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 12788938, 19329485). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function. ClinVar contains an entry for this variant (Variation ID: 233963). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is present in population databases (rs758644748, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 301 of the PTEN protein (p.Asp301Asn).
Mendelics RCV000699550 SCV000838424 uncertain significance PTEN hamartoma tumor syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986006 SCV001134779 uncertain significance not provided 2020-06-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000223261 SCV001342178 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-07 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 301 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 demonstrated a similar impact as wild-type in an AKT phosphorylation assay (PMID: 19329485). This variant has not been reported in individuals affected with hereditary cancer in the literature, but it also affects a Caspase cleavage site in the PTEN protein which may impair the regulation of protein stability (PMID: 12788938). This variant has been identified in 2/251222 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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