ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1018A>C (p.Asn340His) (rs759852661)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589156 SCV000222231 uncertain significance not provided 2014-08-22 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1018A>C at the cDNA level, p.Asn340His (N340H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Asn340His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. PTEN Asn340His occurs at a position that is well conserved across species and is located in C2 tensin-type domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PTEN Asn340His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000473947 SCV000541620 uncertain significance PTEN hamartoma tumor syndrome 2016-05-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 340 of the PTEN protein (p.Asn340His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs759852661, ExAC 0.002%) but has not been reported in the literature in individuals with a PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 189510). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000589156 SCV000696518 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The PTEN c.1018A>C (p.Asn340His) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/120464 control chromosomes at a frequency of 0.0000083, which is approximately 1 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism, however the number of occurrences in this database is very low. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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