rs1554890324

Positions:

• chr10-87864470-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4_Moderate PM6 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: PTEN c.1A>G (p.M1?) meets criteria to be classified as pathogenic 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).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 29752200)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 29752200, 28774669; internal laboratory contributor ClinVar Organization ID: 26957) LINK:https://erepo.genome.network/evrepo/ui/classification/CA377781751/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 6.45

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.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1A>G	p.Met1?	start_lost	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.520A>G	p.Met174Val	missense_variant	2/10		NP_001291646.4
PTEN	NM_001304718.2	c.-705A>G		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1A>G	p.Met1?	start_lost	1/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 22, 2019	PTEN c.1A>G (p.M1?) meets criteria to be classified as pathogenic 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 29752200) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 29752200, 28774669; internal laboratory contributor ClinVar Organization ID: 26957) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 10, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PTEN protein in which other variant(s) (p.Asn12Ile) have been determined to be pathogenic (PMID: 25669429, 29706633; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 484600). Disruption of the initiator codon has been observed in individual(s) with PTEN-related conditions (PMID: 23695273, 27157322, 28600779, 28774669, 29752200). This sequence change affects the initiator methionine of the PTEN mRNA. The next in-frame methionine is located at codon 35. -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 25, 2023

This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2023

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23695273, 25669429, 27157322, 29752200, 28774669) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2017

The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the PTEN gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 35 amino acids from the initiation site. An alternate variant at the initiation codon, c.1A>C (p.M1L), was identified in a high-risk breast and/or ovarian cancer patient from Hong Kong and was considered pathogenic (Kwong A et al. J Mol Diagn, 2016 Jul;18:580-94). Also, another alteration, c.3G>T (p.M1I), was reported in an 11 year old male who had a clinical diagnosis of autism spectrum disorder, macrocephaly, café-au-lait macules, seizure history, oral mucosal papillomatosis, and penile freckling. His 12 year old brother also tested positive for this alteration and he had a clinical diagnosis of ASD as well as macrocephaly, oral mucosal papillomatosis, penile freckling, and seizure history (Hobert JA et al. Eur. J. Hum. Genet., 2014 Feb;22:273-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.71	P
Vest4		0.93
MutPred		0.94		Loss of helix (P = 0.0376);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1554890324; hg19: chr10-89624227;