10-87864513-G-A

Position:

• chr10-87864513-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP2 PS3_Moderate PM6_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.44G>A (p.Arg15Lys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Absent in large sequenced populations (PMID 27535533). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor: SCV000573362.4)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. PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16613142/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: 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.44G>A	p.Arg15Lys	missense_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.563G>A	p.Arg188Lys	missense_variant	2/10		NP_001291646.4
PTEN	NM_001304718.2	c.-662G>A		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.44G>A	p.Arg15Lys	missense_variant	1/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Apr 05, 2024	NM_000314.8(PTEN):c.44G>A (p.Arg15Lys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PM2_P: Absent in large sequenced populations (PMID 27535533). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor: SCV000573362.4) 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. PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (<= -1.11) on a high throughput phosphatase assay (PMID:29706350). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 01, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg15 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21417916, 16773562, 21659347, 24375884, 17942903, 25875300, 29706350). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects PTEN protein function (PMID: 25875300). This variant has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 404147). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 15 of the PTEN protein (p.Arg15Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2017

The R15K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, functional studies show that while R15K does not inhibit nuclear accumulation of PTEN, it does show severely diminished or completely abrogated phosphatase activity in vitro (Gil et al., 2015). The R15K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R15K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and is located within the phosphatase domain and the N-terminal nuclear localization signal (Molinari et al., 2013; Gil et al., 2015). A missense variant in the same residue (R15S) has been reported in the Human Gene Mutation Database in association with Cowden syndrome (Nagy et al., 2011; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, R15K is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.71
MutPred		0.50		Gain of ubiquitination at R15 (P = 0.023);
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.98

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: rs398123324; hg19: chr10-89624270; COSMIC: COSV64297317; COSMIC: COSV64297317;