rs202004587

chr10-87931071-G-Achr10-87931071-G-Cchr10-87931071-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 5P and 9B. PM1 PM2 PP2 BP4 BP6_Very_Strong

The NM_000314.8(PTEN):c.235G>A(p.Ala79Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,605,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:7 B:14
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PTEN
• BP4: Computational evidence support a benign effect (MetaRNN=0.3464243).
• BP6: Variant 10-87931071-G-A is Benign according to our data. Variant chr10-87931071-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41682.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87931071-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.235G>A	p.Ala79Thr	missense_variant	4/9	ENST00000371953.8
PTEN	NM_001304717.5	c.754G>A	p.Ala252Thr	missense_variant	5/10
PTEN	NM_001304718.2	c.-516G>A		5_prime_UTR_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.235G>A	p.Ala79Thr	missense_variant	4/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.0000793 AC: 12 AN: 151248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000118

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250170 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135264

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000134 AC: 195 AN: 1454674 Hom.: 0 Cov.: 29 AF XY: 0.000157 AC XY: 114 AN XY: 723934

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000793 AC: 12 AN: 151248 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 5 AN XY: 73822

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:7 Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Apr 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not provided Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	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) -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Cowden syndrome 1 Pathogenic:1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	AlTemaimi Lab, Faculty of Medicine, Kuwait University	May 19, 2017	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). -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 26, 2022

- -

Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Macrocephaly-autism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

PTEN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2019

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). -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	-0.39	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.48
Sift	Benign	0.58	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	B
Vest4		0.59
MVP		0.98
MPC		1.1
ClinPred		0.13	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.75

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

Other links and lift over

dbSNP: rs202004587; hg19: chr10-89690828; COSMIC: COSV64289985;