ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.914G>A (p.Ser305Asn) (rs587780007)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115591 SCV000184407 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
ClinGen PTEN Variant Curation Expert Panel RCV000467732 SCV000930146 uncertain significance PTEN hamartoma tumor syndrome 2019-03-05 reviewed by expert panel curation PTEN c.914G>A (p.S305N) 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: Absent in large sequenced populations (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_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350)
Color RCV000115591 SCV000292211 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000663305 SCV000786560 uncertain significance Cowden syndrome 1 2018-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764925 SCV000896088 uncertain significance Macrocephaly/autism syndrome; Meningioma, familial; Malignant tumor of prostate; VACTERL association with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212886 SCV000149500 uncertain significance not specified 2017-03-03 criteria provided, single submitter clinical testing This variant is denoted PTEN c.914G>A at the cDNA level, p.Ser305Asn (S305N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Ser305Asn 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 Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. PTEN Ser305Asn occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the C2 Domain (Nguyen 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PTEN Ser305Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586676 SCV000696548 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing Variant summary: The PTEN c.914G>A (p.Ser305Asn) variant located in the C2 domain (via InterPro) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP), and has been reported in one affected individual diagnosed with Lung Cancer, who also carried a EGFR del19 mutation. Multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance."
Invitae RCV000467732 SCV000541582 uncertain significance PTEN hamartoma tumor syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 305 of the PTEN protein (p.Ser305Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 127696). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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