10-87933130-G-A

Position:

• chr10-87933130-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.371G>A​(p.Cys124Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C124R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 19 ACMG points.

• PM1: In a mutagenesis_site Loss of protein phosphatase activity. Unable to inhibit focal adhesion formation. (size 0) in uniprot entity PTEN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87933129-T-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-87933130-G-A is Pathogenic according to our data. Variant chr10-87933130-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.371G>A	p.Cys124Tyr	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.890G>A	p.Cys297Tyr	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-380G>A		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.371G>A	p.Cys124Tyr	missense_variant	5/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 27, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17324556, 20685300]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 28, 2023	Criteria applied: PM5_STR,PS4_MOD,PM1,PM2_SUP,PP2,PP3 -
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 caused by missense variants have been 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. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (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). This residue is annotated as an active and catalytic site within the protein tyrosine phosphatase-like catalytic domain (NCBI). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Multiple alternative changes affecting the same residue have been reported pathogenic in patients with Cowden, hamartoma tumour and hereditary cancer-predisposing syndrome (ClinVar, LOVD). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a patients Cowden syndrome (PMID: 15211648) and has been regarded likely pathogenic in ClinVar for both hamartoma tumour syndrome and hereditary cancer-predisposing syndrome. (SP) 1102 - Strong phenotype match for this individual. (SP) 1207 - Parental origin of the variant is unresolved. Only the mother was tested and is negative. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 124 of the PTEN protein (p.Cys124Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with anaplastic astrocytoma and/or Cowden syndrome (PMID: 15211648, 31970404). ClinVar contains an entry for this variant (Variation ID: 233631). 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. This variant disrupts the p.Cys124 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10555148, 12938083, 17324556, 20685300, 21194675, 21828076, 25647146). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 2022

Identified in an individual with a clinical diagnosis of Cowden syndrome as well as a pediatric patient with anaplastic astrocytoma (Takagai et al., 2001; Sawada et al., 2004; Muskens et al., 2020); Published functional studies demonstrate decreased lipid phosphatase activity (Mighell et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31970404, 15211648, 24475377, 19457929, 29785012, 29706350) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2016

The p.C124Y variant (also known as c.371G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 371. The cysteine at codon 124 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration occurs in a catalytically active residue responsible for dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is critical for tumor suppressor function (Xiao Y et al. Cell Signal. 2007 Jul; 19(7):1434-45. Chia JY et al. Biochim Biophys. Acta 2010 Sep; 1804(9):1785-95). This alteration has been detected in a 39y/o individual suspected to have Cowden syndrome due to the presence of small papules on his fingers, face, neck, and axillary fossae, as well as multiple polyps in his rectum, esophagus, stomach, and duodenum (Sawada T et al. Am J Med Genet A. 2004 Jul 1;128A(1):12-4; Takagaki S et al.Prog Dig Endosc 2001; 59:56-59). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 250000 alleles tested) in our clinical cohort. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of methylation at K125 (P = 0.0183);
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0

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: rs876660535; hg19: chr10-89692887; COSMIC: COSV64290215;