rs587782343

chr10-87933073-G-Achr10-87933073-G-Cchr10-87933073-G-T

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.314G>A(p.Cys105Tyr) 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. 12/20 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. C105W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.52

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain 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 chr10-87933072-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1728081.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 10-87933073-G-A is Pathogenic according to our data. Variant chr10-87933073-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142261.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.314G>A	p.Cys105Tyr	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.833G>A	p.Cys278Tyr	missense_variant	6/10
PTEN	NM_001304718.2	c.-437G>A		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.314G>A	p.Cys105Tyr	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

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	Jun 04, 2021	PTEN c.314G>A (p.Cys105Tyr) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 105 of the PTEN protein (p.Cys105Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Bannayan-Riley-Ruvalcaba syndrome and/or PTEN-related conditions (PMID: 10400993; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 142261). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 15987703). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2022

The p.C105Y variant (also known as c.314G>A) is located in coding exon 5 of the PTEN gene. This alteration results from a G to A substitution at nucleotide position 314. The cysteine at codon 105 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was observed in 1 of 43 individuals who were clinically diagnosed with Bannayan-Riley-Ruvalcaba (BRR) syndrome (Marsh DJ et al. Hum Mol Genet., 1999 Aug;8(8):1461-72). In addition, this alteration has been observed in one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome, where the variant was determined to be the result of a de novo mutation or germline mosaicism, although paternity was not confirmed (Ambry internal data, interlaboratory communication). In one functional study, the PTEN p.C105Y variant showed no interaction with the LKB1 (STK11) protein in a yeast two-hybrid assay (Mehenni H et al. Hum. Mol. Genet., 2005 Aug;14:2209-19). Based on internal structural analysis, C105Y is more disruptive to the phosphatase domain than all nearby internally pathogenic variants, including one at the same position (Dempsey DR et al. Nat Struct Mol Biol., 2021 10;28(10):858-868; Lee CU et al. Angew Chem Int Ed Engl., 2015 Nov;54(46):13796-800). 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). Furthermore, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		Gain of phosphorylation at C105 (P = 0.0879);
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		5.1
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: rs587782343; hg19: chr10-89692830; COSMIC: COSV64290665;