chr10-87960974-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BS1PP2BP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000618/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

9
10

Clinical Significance

Likely benign reviewed by expert panel U:8B:9O:2

Conservation

PhyloP100: 3.74
Variant links:
Genes affected
PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTENNM_000314.8 linkc.882T>G p.Ser294Arg missense_variant Exon 8 of 9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkc.1401T>G p.Ser467Arg missense_variant Exon 9 of 10 NP_001291646.4 P60484
PTENNM_001304718.2 linkc.291T>G p.Ser97Arg missense_variant Exon 8 of 9 NP_001291647.1 P60484

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkc.882T>G p.Ser294Arg missense_variant Exon 8 of 9 1 NM_000314.8 ENSP00000361021.3 P60484-1

Frequencies

GnomAD3 genomes
AF:
0.000257
AC:
39
AN:
151884
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000525
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251176
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461598
Hom.:
0
Cov.:
36
AF XY:
0.0000248
AC XY:
18
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00102
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000257
AC:
39
AN:
151884
Hom.:
0
Cov.:
31
AF XY:
0.000229
AC XY:
17
AN XY:
74182
show subpopulations
Gnomad4 AFR
AF:
0.000725
Gnomad4 AMR
AF:
0.000525
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000136
Hom.:
0
Bravo
AF:
0.000276
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:8Benign:9Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4
Oct 29, 2020
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 01, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 12, 2024
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87960974:T>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BA1'] and an overall classification of Benign -

Sep 24, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:2Benign:1
Jun 27, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

May 21, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 21, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP2 -

PTEN hamartoma tumor syndrome Uncertain:1Benign:2
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 02, 2018
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 04, 2023
Clingen PTEN Variant Curation Expert Panel, Clingen
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

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). -

not specified Uncertain:1Benign:1Other:1
Jul 08, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Jun 16, 2021
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Cowden syndrome 1 Uncertain:2
Apr 05, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 22, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Uncertain:1
Apr 07, 2020
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PP2, BP4 -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Uncertain:1
Apr 16, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PTEN-related disorder Benign:1
Jan 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 Other:1
-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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/. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.
Eigen
Benign
-0.064
Eigen_PC
Benign
0.095
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.080
D
MetaRNN
Benign
0.14
T;T
MetaSVM
Uncertain
0.18
D
MutationAssessor
Benign
1.7
L;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.4
N;.
REVEL
Uncertain
0.36
Sift
Benign
0.054
T;.
Sift4G
Benign
0.15
T;T
Polyphen
0.17
B;.
Vest4
0.58
MutPred
0.52
Gain of catalytic residue at S294 (P = 0.0188);.;
MVP
0.86
MPC
1.6
ClinPred
0.056
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143335584; hg19: chr10-89720731; COSMIC: COSV104426465; API