rs1114167650

Positions:

• chr10-87925562-G-A
• chr10-87925562-G-C
• chr10-87925562-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.209+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTEN NM_000314.8 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.29

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-87925562-G-A is Pathogenic according to our data. Variant chr10-87925562-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 427614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87925562-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.209+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.728+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.-540-5484G>A		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.209+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410832 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 703524

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTEN c.209+5G>A variant was identified in 6 of 238 proband chromosomes (frequency: 0.0252) from individuals or families with Cowden syndrome and Bannayan–Zonana syndrome (Celebi_1999, Chen_2017, Marsh_1998, Plamper_2017). The variant was also identified in dbSNP (ID: rs1114167650) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics and Cleveland Clinic), Clinvitae (2x as in ClinVar), Cosmic (found as a somatic mutation 3 x in the central nervous system, 2 x in the endometrium, 1 x in the lung and 1 x in the kidney), LOVD 3.0 (2x as pathogenic), and Zhejiang Colon Cancer Database (1 x). The variant was not identified in the MutDB database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). A functional study showed the c.209+5G>A variant led to the splicing out of exon 3 in two different patients affected with Cowden syndrome (Agrawal_2005). A microarray study of gene expression analysis in 74 tumours from patients with familial breast cancer found the variant in 4 tumours (Banneau_2010). The variant has also been reported in adolescents with PTEN hamartoma tumour syndrome (Plamper_2017) and in a patient with glioblastoma (Rickert_2009). The c.209+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	Intronic +5 splice site variant demonstrated to result in an in-frame deletion of exon 3, disrupting the critical phosphatase domain and ATP binding motifs (Agarwal 2005, Lobo 2009, Molinari 2014, Chen 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22595938, 10340391, 23695273, 25525159, 31336731, 31784482, 16014636, 18626099, 11071384, 28315423, 32959437, 10232405, 9467011, 20712882, 23335809, 28677221, 19457929, 24475377, 32885271) -

Cowden syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

May 26, 2017

- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change falls in intron 3 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with PTEN-related conditions (PMID: 10232405, 20712882, 23695273; Invitae). This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 427614). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 16014636, 28677221). 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

Jan 31, 2020

The c.209+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the PTEN gene. This alteration has been reported in individuals with clinical features of PTEN hamartoma tumor syndrome (PHTS) and was found to segregate with disease in both Cowden syndrome as well as Bannayan-Riley-Ruvalcaba syndrome families (Marsh DJ et al. Hum Mol Genet. 1998;7(3):507-515; Celebi J et al. Exp Dermatol. 1999 Apr;8(2):134-9; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43; Plamper M et al. Cancers (Basel), 2019 Jul;11). This alteration was also described in four Cowden patients with breast apocrine carcinoma (Banneau G et al. Breast Cancer Res. 2010; 12(4):R63). In addition, RNA studies demonstrated in-frame exon 3 skipping for this variant, which was reported to result in reduced PTEN phosphatase activity in one study (Agrawal S et al. Hum Mol Genet. 2005;14(16):2459-2468; Chen HJ et al. Hum. Mutat. 2017 10;38:1372-137; Ambry internal data). Of note, this mutation has been referred to as IVS3+5G>A in some literature. Based on the available information, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1114167650; hg19: chr10-89685319; COSMIC: COSV64290349;