rs121909229

Positions:

• chr10-87933148-G-A
• chr10-87933148-G-C
• chr10-87933148-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS3 PS4 PM1 PP2 PM2 PM6

This summary comes from the ClinGen Evidence Repository: PTEN c.389G>A (p.R130Q) meets criteria to be classified as pathogenic 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).PM6_VS: At least four assumed de novo observations in a patient with the disease and no family history. (PMID 22595938, PMID 22327138, internal laboratory contributor(s) SCV000222111.11)PS3: Phosphatase activity <50% of wild type (PMID 10866302)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 26798346, PMID 17526801, PMID 23335809, PMID 22266152)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000437/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:32 O:1
• Conservation: PhyloP100: 9.53

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 Pathogenic. Variant got 15 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.389G>A	p.Arg130Gln	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.908G>A	p.Arg303Gln	missense_variant	6/10
PTEN	NM_001304718.2	c.-362G>A		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.389G>A	p.Arg130Gln	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2022	Published functional studies demonstrate a damaging effect: reduced phosphatase activity and increased pAKT levels (Han et al., 2000; Andrs-Pons et al., 2007; Mighell et al., 2018; Wang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20600018, 23335809, 22266152, 14574156, 15067177, 22327138, 28790115, 28683746, 10555148, 24475377, 19457929, 9915974, 22320991, 21822720, 27221918, 17526801, 22252256, 10866302, 24766807, 23470840, 16773562, 26798346, 23399955, 22595938, 29030356, 26800850, 28927094, 28741734, 28424201, 28119489, 28536309, 28407039, 28395087, 29359449, 28152038, 28475857, 27477328, 17942903, 31336731, 31006514, 29663862, 29729901, 29706350, 30528446, 33258288, 33509259, 29152901, 31594918, 33077954, 30787465) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PTEN: PS4, PM1, PM2, PM5, PM6, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Cowden syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ­hamartoma tumour syndrome. Loss of function is the mechanism for null variants while missense variants have been proven to exert either a loss of function or dominant-negative mechanism (PMID: 20301661). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (PMID: 20301661). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg130Leu) and p.(Arg130Pro) have been observed by several clinical laboratories in ClinVar and clasified as pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has a three star entry in ClinVar and has been classified as pathogenic by an expert panel (ClinGen). It has also been observed by other clinical laboratories in ClinVar and seen in the literature in at least one confirmed de novo case (PMID: 22595938). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 27, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 32350270]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21194675, 21190448, 22266152, 23399955, 32442409]. -

PTEN hamartoma tumor syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 130 of the PTEN protein (p.Arg130Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 9915974, 21822720, 22327138, 23399955, 23470840). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7829). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 17942903). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	PTEN c.389G>A (p.R130Q) meets criteria to be classified as pathogenic 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). PM6_VS: At least four assumed de novo observations in a patient with the disease and no family history. (PMID 22595938, PMID 22327138, internal laboratory contributor(s) SCV000222111.11) PS3: Phosphatase activity <50% of wild type (PMID 10866302) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 26798346, PMID 17526801, PMID 23335809, PMID 22266152) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2019	The p.Arg130Gln variant in PTEN has been reported as a germline variant in >20 individuals with features of PTEN Hamartoma Tumor syndrome (Chang 2016, Langer 2015, Ngeow 2014, Ngeow 2013, Busch 2013, Bubien 2013, Mester 2012, O'Rourke 2012, Heindl 2012, Baig 2011, Villeneuve 2011, Pilarski 2011, Yang 2010, Lobo 2009, Kurose 1999). At least 2 of these individuals had no family history and were assumed de novo (Mester 2012, O'Rourke 2012). This variant was absent from large population studies. It was classified as Pathogenic on October 18, 2017 by the ClinGen-approved PTEN Variant Curation Expert Panel (Variation ID 7829). It is located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel, and additional variants involving this codon (including p.Arg130Leu) have been identified in individuals with PTEN Hamartoma Tumor syndrome and are classified as likely pathogenic/pathogenic by several clinical labs in ClinVar. In vitro functional studies support an impact on protein function (Han 2000, Rodriguez-Escudero 2011). In summary, the p.Arg130Gln variant in PTEN meets criteria to be classified as pathogenic for autosomal dominant PTEN Hamartoma Tumor syndrome. ACMG/AMP Criteria applied: PM6_Strong, PP2, PM1, PM2, PS4, PS3_Supporting, PM5. -

Ovarian neoplasm Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Cowden syndrome Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2022	Variant summary: PTEN c.389G>A (p.Arg130Gln) results in a conservative amino acid change located in the Tyrosine-specific protein phosphatases domain (IPR000387) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.389G>A has been reported in the literature in multiple individuals affected with Cowden Syndrome/PTEN Hamartoma Tumor Syndrome (e.g. Tan_2011), including individuals in which the variant occurred de novo (e.g. Mester_2012). These data indicate that the variant is very likely to be associated with disease. Experimentally, an in vitro phosphatase assay determined that the variant had no phosphatase activity; the variants performance was equal to background levels seen with empty vector (Han_2000). Ten ClinVar submitters, including one expert panel, have assessed the variant since 2014: nine submitters (including ClinGen PTEN Variant Curation Expert Panel) classified the variant as pathogenic, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 06-23-2010 by Lab GeneDx. 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/. -

Small cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Papillary renal cell carcinoma type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2021

The p.R130Q pathogenic mutation (also known as c.389G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 389. The arginine at codon 130 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been well described in the literature in a number of individuals of varying backgrounds with classic features of PTEN Hamartoma Tumor Syndrome (PHTS) or early onset breast cancer (Baig RM et al. Asian Pac. J. Cancer Prev. 2011;12(10):2773-8; Busch RM et al. Genet. Med. 2013 Jul;15(7):548-53; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15; Heindl M et al. Gastroenterology. 2012 May;142(5):1093-1096.e6; Kurose K et al. Am. J. Hum. Genet. 1999 Jan;64(1):308-10; Lobo GP et al. Hum. Mol. Genet., 2009 Aug;18:2851-62; Pilarski R et al. J. Med. Genet. 2011 Aug;48(8):505-12). This alteration was also identified as a de novo mutation in a female diagnosed with macrocephaly, goiter, uterine fibriods, and breast cancer at the age of 29 (Mester J et al. Genet. Med., 2012 Sep;14:819-22). Functional studies performed with this variant demonstrated reduced relative phosphatase activity and altered cellular localization compared to the wild type PTEN protein (Han SY et al. Cancer Res., 2000 Jun;60:3147-51; Lobo GP et al. Hum. Mol. Genet., 2009 Aug;18:2851-62). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of methylation at R130 (P = 0.0398);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.99

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: rs121909229; hg19: chr10-89692905; COSMIC: COSV64288376;