rs587780007

chr10-87961006-G-Achr10-87961006-G-Cchr10-87961006-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000314.8(PTEN):c.914G>A(p.Ser305Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S305G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:11
• Conservation: PhyloP100: 5.66

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PTEN
• BP4: Computational evidence support a benign effect (MetaRNN=0.34556162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.914G>A	p.Ser305Asn	missense_variant	8/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1433G>A	p.Ser478Asn	missense_variant	9/10
PTEN	NM_001304718.2	c.323G>A	p.Ser108Asn	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.914G>A	p.Ser305Asn	missense_variant	8/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461620 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 305 of the PTEN protein (p.Ser305Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital hydrocephalus (PMID: 33077954). ClinVar contains an entry for this variant (Variation ID: 127696). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 05, 2019	PTEN c.914G>A (p.S305N) is currently classified as a variant of uncertain significance 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). 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. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces serine with asparagine at codon 305 of the PTEN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2023	This missense variant replaces serine with asparagine at codon 305 of the PTEN protein. In a massively parallel functional assay, this variant did not demonstrate a significant defect in lipid phosphatase activity (PMID: 29706350). In a cohort of individuals affected with congenital hydrocephalus, this variant was reported in an individual affected with macrocephaly, cerebellar tonsillar ectopia and neurodevelopmental delay (PMID: 33077954). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2021	The c.914G>A (p.S305N) alteration is located in exon 8 (coding exon 8) of the PTEN gene. This alteration results from a G to A substitution at nucleotide position 914, causing the serine (S) at amino acid position 305 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cowden syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 31, 2023

Variant summary: PTEN c.914G>A (p.Ser305Asn) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.914G>A has been reported in the literature in an individual affected with non-small cell lung cancer who also carried a EGFR del19 mutation which is associated with responsiveness to Tyrosine kinase inhibitors (example: Kim_2014). This variant has also been identified as an inherited variant in an individual with Aqueductal stenosis, macrocephaly, cerebellar tonsillar ectopia and neurodevelopmental delay through WES (example: Jin_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function through a large-scale in vitro assay (Mighell_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 33077954, 24468202, 29706350, 15492994). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of prostate;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C1959582:PTEN hamartoma tumor syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital hydrocephalus, macrocephaly, cerebellar tonsillar ectopia, and neurodevelopmental delay (Jin 2020); Published functional studies demonstrate wildtype-like phosphatase activity (Mighell 2018); This variant is associated with the following publications: (PMID: 24468202, 15492994, 18626510, 33077954, 29706350) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.26
Sift	Benign	0.23	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;.
Vest4		0.58
MutPred		0.35		Loss of phosphorylation at S305 (P = 0.0302);.;
MVP		0.85
MPC		1.1
ClinPred		0.77	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.60

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: rs587780007; hg19: chr10-89720763; COSMIC: COSV64290110;