ClinVar Genomic variation as it relates to human health

NM_000314.8(PTEN):c.882T>G (p.Ser294Arg) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Filtering allele frequency of 0.0002887 (0.02887%, 13/24922 African/African American alleles) in gnomAD. BP4: REVEL score = 0.365. 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. Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID: 29300386): BS1 (-4 pts), BP4 (-1 pt), PP2 (+1 pt) = -4 pts total (Likely Benign).

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast or colorectal cancer (Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 23161105, 29785012, 24728327, 26800850, 28135145, 27720647, 29272070, 25186627, 33796447, 33887726, 18626510)

Variant summary: PTEN c.882T>G (p.Ser294Arg) results in a non-conservative amino acid change located in the Tensin phosphatase, C2 domain (IPR014020) of 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 5.3e-05 in 1614844 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (1.6e-05). c.882T>G has been reported in the literature in individuals affected with various types of cancers including but not limited to neuroblastoma, colorectal cancer and prostate cancer (example: Zhang_2015, Yurgelun_2017, Coelho_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 25186627, 28135145, 26580448, 26800850, 23161105, 38311546). ClinVar contains an entry for this variant (Variation ID: 127693). Based on the evidence outlined above, the variant was classified as likely benign.

DNA sequence analysis of the PTEN gene demonstrated a sequence change, c.882T>G, in exon 8 that results in an amino acid change, p.Ser294Arg. This sequence change has been described in the gnomAD database with a frequency of 0.052% in the African American/African subpopulation (dbSNP rs143335584). The p.Ser294Arg change affects a moderately conserved amino acid residue located in a domain of the PTEN protein that is known to be functional. The p.Ser294Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with colorectal cancer who underwent germline genetic testing and it was considered a variant of unknown significance (PMID: 28135145). Due insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser294Arg change remains unknown at this time.

ACMG classification criteria: PP2, BP4

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

PP2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Variant classified as Uncertain significance and reported on 11-19-2020 by USAF Medical Genetics Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.