ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.235G>A (p.Ala79Thr) (rs202004587)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000123046 SCV000840467 likely benign PTEN hamartoma tumor syndrome 2018-04-06 reviewed by expert panel curation PTEN c.235G>A (p.A79T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Allele frequency of 0.0045 (0.45%, 9/1984 alleles) in the GME variome. (PMID 27428751) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000222198.12) 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.
Invitae RCV000123046 SCV000166341 benign PTEN hamartoma tumor syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129085 SCV000183790 likely benign Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000034594 SCV000222198 likely benign not provided 2020-09-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 26800850, 25980754, 25669429, 30728895, 12789288, 25527629, 10923032, 21659347, 21956414, 16171945, 23161105, 12372056, 21343951, 27720647, 27600092, 11297763, 24142049, 9619835, 21194675, 27477328, 28007035, 25925381, 22076652, 28873162, 29641532, 29371908, 29785012, 29706350, 31159747, 31209962, 31144778, 32350270, 32366478)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000123046 SCV000257666 uncertain significance PTEN hamartoma tumor syndrome 2015-07-10 criteria provided, single submitter clinical testing
Counsyl RCV000409443 SCV000487786 uncertain significance Cowden syndrome 1 2015-11-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515193 SCV000611427 uncertain significance Endometrial carcinoma; Macrocephaly/autism syndrome; Meningioma, familial; Squamous cell carcinoma of the head and neck; Bannayan-Riley-Ruvalcaba syndrome; Malignant tumor of prostate; Thyroid cancer, nonmedullary, 2; VACTERL association with hydrocephalus; Glioma susceptibility 2; Cowden syndrome 1; Cutaneous malignant melanoma 1 2017-05-23 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000626250 SCV000746903 uncertain significance Macrocephaly/autism syndrome 2017-12-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034594 SCV000806056 uncertain significance not provided 2014-09-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129085 SCV000822140 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000123046 SCV000838417 uncertain significance PTEN hamartoma tumor syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034594 SCV000888591 likely benign not provided 2019-04-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129085 SCV000902713 likely benign Hereditary cancer-predisposing syndrome 2020-06-03 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Strasbourg University Hospital RCV001257777 SCV001434590 uncertain significance Intellectual disability 2020-04-20 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034594 SCV000043462 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
AlTemaimi Lab, Faculty of Medicine,Kuwait University RCV000409443 SCV000577862 pathogenic Cowden syndrome 1 2017-05-19 no assertion criteria provided clinical testing CMT panel and gene duplication assays were negative and investigative exome sequencing was conducted. Clinical presentation is 80% match with Cowden Syndrome (exception unilateral pes cavus).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357785 SCV001553361 likely benign Carcinoma of colon no assertion criteria provided clinical testing The PTEN p.Ala79Thr variant was identified in 10 of 47,988 proband chromosomes (frequency: 0.0002) from individuals or families with Bannayan-Riley Ruvalcaba syndrome, Cowden syndrome, PTEN hamartoma tumour syndrome, Lynch Syndrome, or ovarian or breast cancer and was present in 2 of 23,624 control chromosomes (frequency: 0.00008) from healthy individuals (Momozawa 2018, Figer 2002, Pilarski 2011, Tan 2011, Mester 2011, Dominguez-Valentin 2018, Nizialek 2015, Yurgelun 2015, Ngeow 2011). The variant was identified in dbSNP (rs202004587) as “with uncertain significance allele”, ClinVar (classified as likely benign by ClinGen PTEN Expert Panel in 2018, Ambry Genetics, GeneDx, and Color; as uncertain significance by Invitae, PreventionGenetics, Counsyl and 7 other submitters; and as pathogenic by Kuwait University) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 29 of 281,404 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 22 of 128,158 chromosomes (freq: 0.0002), South Asian in 5 of 30,560 chromosomes (freq: 0.0002), and Other in 1 of 7170 chromosomes (freq: 0.00004), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian or Finnish populations. However, this variant was also identified at an allele frequency of 0.005 in a Middle Eastern population, increasing the likelihood this could be a low frequency benign variant (Scott 2016). This variant has been identified in the homozygous state in one unaffected individual, decreasing the likelihood that this variant has clinical significance (PTEN expert panel internal data, per ClinVar entry dated April 6, 2018). The p.Ala79 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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