rs1554900635

Variant names:

• chr10-87952218-T-A
• rs1554900635
• NM_000314.8:c.593T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-87952218-T-A
• chr10-87952218-T-C
• chr10-87952218-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001304718.2(PTEN):​c.2T>A​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_001304718.2 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 2 codons. Genomic position: 87952220. Lost 0.006 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87952218-T-A is Pathogenic according to our data. Variant chr10-87952218-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468702.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.593T>A	p.Met198Lys	missense_variant	Exon 6 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2	c.2T>A	p.Met1?	start_lost	Exon 6 of 9		NP_001291647.1
PTEN	NM_001304717.5	c.1112T>A	p.Met371Lys	missense_variant	Exon 7 of 10		NP_001291646.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.593T>A	p.Met198Lys	missense_variant	Exon 6 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 198 of the PTEN protein (p.Met198Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PTEN Hamartoma tumor syndrome (PHTS) (PMID: 22266152; internal data). ClinVar contains an entry for this variant (Variation ID: 468702). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.025	D;.
Sift4G	Uncertain	0.038	D;D
Polyphen		0.30	B;.
Vest4		0.98
MutPred		0.70		Gain of ubiquitination at M198 (P = 0.0388);.;
MVP		0.98
MPC		2.0
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.98

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: rs1554900635; hg19: chr10-89711975; COSMIC: COSV64288507;