10-87864509-A-G

Position:

• chr10-87864509-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS3_Supporting PP2 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.40A>G (p.Arg14Gly) is currently classified as a variant of uncertain significance 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).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:28526761)PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. Mingo et al. 2018 (PMID:29706633).PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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: in silico REVEL score of 0.811 (>0.7) LINK:https://erepo.genome.network/evrepo/ui/classification/CA377781914/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2 O:1
• Conservation: PhyloP100: 6.39

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 Uncertain_significance. Variant got 5 ACMG points.

• 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.40A>G	p.Arg14Gly	missense_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.559A>G	p.Arg187Gly	missense_variant	2/10		NP_001291646.4
PTEN	NM_001304718.2	c.-666A>G		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.40A>G	p.Arg14Gly	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: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Aug 04, 2023	NM_000314.8(PTEN):c.40A>G (p.Arg14Gly) is currently classified as a variant of uncertain significance 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). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:28526761) PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. Mingo et al. 2018 (PMID: 29706633). PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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: in silico REVEL score of 0.811 (>0.7) -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The p.R14G variant (also known as c.40A>G), located in coding exon 1 of the PTEN gene, results from an A to G substitution at nucleotide position 40. The arginine at codon 14 is replaced by glycine, an amino acid with dissimilar properties. This variant demonstrated wildtype-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was wildtype-like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). However, in another functional study, lipid phosphatase activity for this variant was reduced compared to wild type PTEN and subcellular localization was reportedly similar to wild type PTEN (Mingo J et al. Eur J Hum Genet, 2018 Aug;26:1180-1187). This alteration was identified in a 4 year old female with macrocephaly, ASD, developmental delay and hypothyroidism, as well as in her mother with macrocephaly and hypothyroidism (Hansen-Kiss E et al. J Med Genet, 2017 Jul;54:471-478). Based on internal structural analysis, p.R14G disrupts a residue within the NLS motif key to localization (Ambry internal data; Das S et al. Proc Natl Acad Sci U S A, 2003 Jun;100:7491-6; Gil A et al. PLoS One, 2015 Apr;10:e0119287; Dempsey DR et al. Nat Struct Mol Biol, 2021 Oct;28:858-868). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Other:1

not provided, no classification provided

clinical testing

GeneDx

-

This A>G nucleotide substitution results in the replacement of an Arginine codon (AGG) with a Glycine codon (GGG) at amino acid position 14, and is denoted c.40A>G at the cDNA level or p.R14G at the protein level. The novel R14G missense change has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, the R14G amino acid substitution has previously been reported as a somatic change in two colon tumors and one kidney tumor among other tumor types according to the Catalogue of Somatic Mutations in Cancer. The NHLBI ESP Exome Sequencing Project reports R14G was not observed in approximately 6500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The R14G variant is a non-conservative substitution as a positively-charged Arginine residue is replaced by a neutral Glycine residue at a position that is evolutionarily well-conserved. This amino acid substitution is located within the phosphatase tensin-type domain, a known functional domain. missense pathogenic variants in nearby positions have been reported in the literature, according to HGMD (K13E, R15S, D22G). Therefore, R14G is a strong candidate for a disease-causing mutation likely associated with a PTEN-related disorder; however the possibility that it is a benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.81
Sift	Benign	0.066	T
Sift4G	Benign	0.091	T
Polyphen		0.25	B
Vest4		0.92
MutPred		0.55		Loss of MoRF binding (P = 0.0365);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085308047; hg19: chr10-89624266; COSMIC: COSV64289619; COSMIC: COSV64289619;