ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) (rs375709098)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000205690 SCV000886865 uncertain significance PTEN hamartoma tumor syndrome 2018-11-28 reviewed by expert panel curation PTEN c.1061C>A (p.Pro354Gln) 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). 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, 29785012)
Ambry Genetics RCV000132539 SCV000187636 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-29 criteria provided, single submitter clinical testing The p.P354Q variant (also known as c.1061C>A), located in coding exon 9 of the PTEN gene, results from a C to A substitution at nucleotide position 1061. The proline at codon 354 is replaced by glutamine, an amino acid with similar properties. This alteration has been reported in multiple individuals with features suspicious, but not diagnostic, for Cowden syndrome (Tan M et al. Am. J. Hum. Genet. 2011 Jan;88:42-56; Mester J et al. Eur. J. Hum. Genet. 2011 Jul;19:763-8; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). In a high throughput, multiplex assay designed to measure the steady-state abundance of protein variants in cultured human cells, this variant had wild type-like protein abundance (Matreyek KA et al. Nat. Genet., 2018 Jun;50:874-882). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000513025 SCV000222169 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1061C>A at the cDNA level, p.Pro354Gln (P354Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). Mester et al. (2011) reported this variant occurring in two related individuals with features of Cowden syndrome, however neither met International Cowden Syndrome Consortium diagnostic criteria. Pilarski et al. (2011) reported an additional patient with this variant identified through clinical PTEN testing. Yurgelun et al. (2015) identified this variant in an individual undergoing multi-gene cancer panel testing based on a history of a Lynch syndrome-related cancer and/or polyps; this particular individual was also found to harbor a pathogenic MSH2 variant. Lastly, this variant was observed in an individual with neuroblastoma and in an individual with a personal and family history of breast cancer (Zhang 2015, Caminsky 2016). PTEN Pro354Gln was observed at an allele frequency of 0.016% (19/122,896) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PTEN Pro354Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205690 SCV000260548 benign PTEN hamartoma tumor syndrome 2020-11-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210607 SCV000263012 uncertain significance Inborn genetic diseases 2015-10-05 criteria provided, single submitter clinical testing
Counsyl RCV000409006 SCV000488776 uncertain significance Cowden syndrome 1 2016-06-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513025 SCV000608561 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000201314 SCV000696524 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: PTEN c.1061C>A (p.Pro354Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 244884 control chromosomes. The observed variant frequency is approximately 13.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.1061C>A has been reported in the literature in sequencing studies of individuals affected with gliomas (Caldera_2011, tumor sequencing of large cell carcinomas (Karlsson_2015), PTEN Hamartoma Tumour Syndrome (Mester_2011), PTEN clinical testing cohort (Pilarski_2011), individuals meeting relaxed Cowden syndrome criteria (Tan_2011), LS clinical testing cohort (Yurgelun_2015), an unpublished case report of an individual undergoing diagnostic exome sequencing with an unrelated phenotype who's unaffected mother and brother carried the variant of interest (Tsang_2015) and as a variant that was excluded from a case control study analysis due to low penetrance (Couch_2018). At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.2047G>A, p.Gly683Arg), providing supporting evidence for a benign role (Yurgelun_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One expert panel (ClinGen PTEN Variant Curation Expert panel) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance, some reporting overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant retained its classification as uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000513025 SCV000704628 uncertain significance not provided 2016-12-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000201314 SCV000711737 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing The p.Pro354Gln variant in PTEN has been reported in 6 individuals with a clinical diagnosis or features of PTEN hamartoma tumor syndrome and segregated with disease in at least 1 affected relative (Mester 2011, Pilarski 2011, Tan 2011, Nizialek 2015, Zhang 2015, Caminsky 2016). This variant was also reported in 1 individual with features of Lynch syndrome, who also carried a pathogenic variant in MSH2 (Yurgelun 2015). Other clinical laboratories have reported this variant in ClinVar (Variation ID: 143020). It has also been identified in 21/270810 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro354Gln variant is uncertain. the ACMG/AMP criteria applied: PS4_Moderate, BP5.
PreventionGenetics,PreventionGenetics RCV000513025 SCV000806058 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513025 SCV000889800 uncertain significance not provided 2020-03-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132539 SCV000910731 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing This missense variant replaces proline with glutamine at codon 354 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional assays have been reported this variant protein to be functional in a lipid phosphatase assay with a fitness score resembling those of synonymous variants (PMID: 29706350) and in protein stability/abundance assay where the variant resulted in WT-like abundance (PMID: 29785012). This variant has been reported in individuals suspected of Cowden syndrome (PMID: 21659347, 25669429) and Lynch syndrome (PMID: 25980754), or affected with breast/ovarian cancer (PMID: 21343951, 26898890), neuroblastoma (PMID: 26580448) and lung cancer (PMID: 26124082). This variant has been identified in 21/276260 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000201314 SCV000692023 uncertain significance not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357175 SCV001552553 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PTEN p.Pro354Gln variant was identified in 8 of 20700 proband chromosomes (frequency: 0.0004) from individuals or families with Cowden syndrome, Neuroblastoma, lynch syndrome, breast or ovarian cancer and was not identified in 222 control chromosomes from healthy individuals (Tan 2011, Zhang 2015, Pilarski 2011, Mester 2011, Yurgelun 2015, Nizialek 2015, Caminsky 2016). The variant was also identified in dbSNP (ID: rs375709098) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl and 5 clinical laboratories), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 21 of 270810 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23476 chromosomes (freq: 0.0001), European in 19 of 122896 chromosomes (freq: 0.0002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro354 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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