10-87966988-T-C

Variant names:

• chr10-87966988-T-C
• rs701848
• NM_000314.8:c.*1516T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000314.8(PTEN):​c.*1516T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 218,680 control chromosomes in the GnomAD database, including 15,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9528 hom., cov: 24)
  • Exomes 𝑓: 0.39 (5779 hom.)
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.32
• Publications: 59 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-87966988-T-C is Benign according to our data. Variant chr10-87966988-T-C is described in ClinVar as Benign. ClinVar VariationId is 301463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.*1516T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.*1516T>C		3_prime_UTR_variant	Exon 10 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.*1516T>C		3_prime_UTR_variant	Exon 9 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.*1516T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.341 AC: 49462 AN: 145100 Hom.: 9530 Cov.: 24

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.394 AC: 28976 AN: 73494 Hom.: 5779 Cov.: 0 AF XY: 0.398 AC XY: 13549 AN XY: 34062

African (AFR) AF: 0.150 AC: 503 AN: 3352

American (AMR) AF: 0.350 AC: 773 AN: 2206

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1636 AN: 4536

East Asian (EAS) AF: 0.431 AC: 4540 AN: 10538

South Asian (SAS) AF: 0.653 AC: 422 AN: 646

European-Finnish (FIN) AF: 0.515 AC: 239 AN: 464

Middle Eastern (MID) AF: 0.336 AC: 150 AN: 446

European-Non Finnish (NFE) AF: 0.409 AC: 18454 AN: 45166

Other (OTH) AF: 0.368 AC: 2259 AN: 6140

GnomAD4 genome AF: 0.341 AC: 49456 AN: 145186 Hom.: 9528 Cov.: 24 AF XY: 0.349 AC XY: 24459 AN XY: 70168

African (AFR) AF: 0.151 AC: 5972 AN: 39432

American (AMR) AF: 0.347 AC: 4854 AN: 13970

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1169 AN: 3428

East Asian (EAS) AF: 0.424 AC: 2104 AN: 4968

South Asian (SAS) AF: 0.639 AC: 2934 AN: 4590

European-Finnish (FIN) AF: 0.447 AC: 3948 AN: 8836

Middle Eastern (MID) AF: 0.273 AC: 77 AN: 282

European-Non Finnish (NFE) AF: 0.409 AC: 27307 AN: 66784

Other (OTH) AF: 0.319 AC: 636 AN: 1996

Alfa AF: 0.267 Hom.: 1106

Bravo AF: 0.320

Asia WGS AF: 0.470 AC: 1624 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs701848; hg19: chr10-89726745; COSMIC: COSV64293119;