rs786202517

chr10-87894050-GG-AC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PP2 PP3 PP5_Very_Strong

The NM_000314.8(PTEN):c.105_106delinsAC(p.Met35_Gly36delinsIleArg) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.42

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 16 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2573307
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000314.8
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 10-87894050-GG-AC is Pathogenic according to our data. Variant chr10-87894050-GG-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.105_106delinsAC	p.Met35_Gly36delinsIleArg	missense_variant	2/9	ENST00000371953.8
PTEN	NM_001304717.5	c.624_625delinsAC	p.Met208_Gly209delinsIleArg	missense_variant	3/10
PTEN	NM_001304718.2	c.-601_-600delinsAC		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.105_106delinsAC	p.Met35_Gly36delinsIleArg	missense_variant	2/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2020

Not observed in large population cohorts (Lek 2016); Observed in individuals referred for multi-gene panel testing (LaDuca 2017); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28152038) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2014

The c.105_106delGGinsAC pathogenic mutation , located in coding exon 2 of the PTEN gene, results from deletion of GG and insertion of AC at nucleotide positions 105 and 106, causing the substitution of two highly-conserved amino acids at codons 35 (methionine to isoleucine) and 36 (glycine to arginine). The p.G36R alteration was first described in an individual with classic Cowden syndrome (CS) and shown to result in abolished PTEN activity in vivo (Celebi JT, Exp. Dermatol. 2000 Apr; 9(2):152-6; Rodríguez-Escudero I, Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). Amino acid substitutions impacting the methionine at codon 35 have been reported as pathogenic in CS and Proteus-like syndrome kindreds and also correlated with loss of PTEN activity (Zhou X, Lancet 2001 Jul; 358(9277):210-1; Tan MH, Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Rodríguez-Escudero I, Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). 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 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 51000 alleles tested) in our clinical cohort. Based on the available evidence, c.105_106delGGinsAC is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786202517; hg19: chr10-89653807;