10-87894048-A-G

Position:

• chr10-87894048-A-G

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PS3_Supporting PS2 PP3 PP2 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.103A>G (p.Met35Val) meets criteria to be classified as Pathogenic 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).PS2_VS: At least two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributors: SCV000275912.7, SCV000565444.8).PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3 (Post et al. 2020 PMID:32350270: pAKT levels similar to C124S).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:27531073, internal laboratory contributor: SCV000275912.7).PM2_P: 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.PP3: REVEL score > 0.7 (score of this variant =0.953) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10578906/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_001304718.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 8.78

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]

PTEN (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 9 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.103A>G	p.Met35Val	missense_variant	2/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2	c.-603A>G		5_prime_UTR_premature_start_codon_gain_variant	2/9		NP_001291647.1
PTEN	NM_001304717.5	c.622A>G	p.Met208Val	missense_variant	3/10		NP_001291646.4
PTEN	NM_001304718.2	c.-603A>G		5_prime_UTR_variant	2/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.103A>G	p.Met35Val	missense_variant	2/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the PTEN protein (p.Met35Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 21194675, 26468640, 27531073, 30311380; external communication). ClinVar contains an entry for this variant (Variation ID: 231916). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 32350270). This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425889, 17942903, 21828076, 25875300). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Feb 09, 2024	NM_000314.8(PTEN):c.103A>G (p.Met35Val) meets criteria to be classified as Pathogenic 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). PS2_VS: At least two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributors: SCV000275912.7, SCV000565444.8). PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3 (Post et al. 2020 PMID: 32350270: pAKT levels similar to C124S). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 27531073, internal laboratory contributor: SCV000275912.7). PM2_P: 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. PP3: REVEL score > 0.7 (score of this variant =0.953) -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 31, 2024	The c.103A>G (p.Met35Val) variant, located on the exon 2 of the PTEN gene, replaces methionine with valine at codon 35 of the PTEN protein (p.Met35Val). This variant has been observed in individuals with PTEN hamartoma tumor syndrome (PHTS) or Cowden syndrome (CS) (PMID: 20600018, 21194675, 26468640, 27531073). This alteration has also been identified as de novo in an individual with clinical features of PHTS (ClinVar Accession ID: SCV001178150.4). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score 0.903). Alteration affecting the same amino acid c.104T>G (p.Met35Arg) has been classified as pathogenic by PTEN Expert Panel (ClinVar ID: 7825). In addition, this variant is absent in the general population database according to gnomAD. 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. Therefore, the c.103A>G (p.Met35Val) variant in the PTEN gene has been classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2023	Published functional studies demonstrate a damaging effect: loss of ability to dephosphorylate pAKT and increased nuclear localization compared to wildtype (Post et al., 2020; Chao et al., 2021); 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 11476841, 27566247, 17427195, 34490615, 29785012, 9425889, 21828076, 26468640, 20600018, 23949151, 11939587, 25669429, 17392703, 19265751, 17286265, 11238682, 15805158, 30311380, 25132236, 25022750, 17942903, 10555148, 25875300, 29706350, 27531073, 21194675, 33509259, 31031587, 31594918, 32350270, 35241692, 33879063, 24475377) -

Cowden syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and dominant-negative are known mechanisms of disease in this gene and are associated with PTEN-related disease (OMIM). Loss of function has been associated with Cowden syndrome 1 (MIM#158350), Lhermitte-Duclos syndrome (MIM#158350) and macrocephaly/autism syndrome (MIM#605309) (PMID: 30311380). Dominant-negative has also been associated with missense variants associated with Cowden syndrome 1 and cancer (PMID: 24766807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported for Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and PTEN-related Proteus syndrome (PMID: 17526800; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (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) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants (p.(Met35Leu), p.(Met35Thr)) have been reported as likely pathogenic, and observed in individuals with Cowden syndrome (CS) or Proteus syndrome (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic, and observed in individuals with CS or PTEN hamartoma tumour syndrome (ClinVar, PMID: 30311380, PMID: 27531073). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 26, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32442409, 26468640, 30311380]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 29, 2024	The p.M35V variant (also known as c.103A>G), located in coding exon 2 of the PTEN gene, results from an A to G substitution at nucleotide position 103. The methionine at codon 35 is replaced by valine, an amino acid with highly similar properties. This alteration, as well as another alteration at the same codon (p.M35T), have previously been reported in individuals meeting clinical criteria for PTEN hamartoma tumor syndrome (PHTS) or relaxed International Cowden Consortium operational criteria for Cowden syndrome (Heald B et al. Gastroenterology. 2010 Dec;139:1927-33; Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Hagelstrom RT et al. Pediatr Blood Cancer. 2016 Mar;63:544-6; Driessen GJ et al. J. Allergy Clin. Immunol. 2016 12;138:1744-1747.e5; Ambry internal data). This alteration has also been identified as de novo in an individual with clinical features of PHTS (Ambry internal data; Mester JL et al. Hum Mutat. 2018 Nov;39(11):1581-1592). Furthermore, another alteration at this codon (p.M35R) has also been reported in an individual with juvenile polyposis syndrome, and yeast in vivo activity was noted to be reduced (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on internal structural analysis, the p.M35V alteration is expected to result in general structural destabilization of the phosphatase domain (Lee JO et al. Cell. 1999 Oct;99:323-34). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2020	This missense variant replaces methionine with valine at codon 35 of the PTEN protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Cowden Syndrome (PMID: 26468640), PTEN hamartoma tumor syndrome (PMID: 27531073) and endometrial cancer (PMID: 23949151). This variant has also been reported in an individual suspected of having Cowden Syndrome (PMID: 21194675). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial meningioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 05, 2018

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PS1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.95
MutPred		0.92		Loss of sheet (P = 0.1158);
MVP		1.0
MPC		3.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -30

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

Publications

LitVar

Other links and lift over

dbSNP: rs876659443; hg19: chr10-89653805; COSMIC: COSV64291926;