10-87863385-C-T

Variant names:

• chr10-87863385-C-T
• rs538728843
• NM_001126049.2:c.-898G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP2 BS2_Supporting BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.-1084C>T (NC_000010.10:g.89623142C>T) meets criteria to be classified as likely benign 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).BS1: Allele frequency of 0.0025 (0.25%, 38/14,966 alleles) in the European subpopulation of the gnomAD cohort. (PMID 27535533)BP2: At least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (internal laboratory contributor(s) SCV000149464.4)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (PMID 27884173, internal laboratory contributor(s) SCV000149464.4, SCV000185343.1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151479/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (7 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:11
• Conservation: PhyloP100: 0.291
• Publications: 3 publications found

Genes affected

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

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

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	NM_001126049.2	MANE Select	c.-898G>A		5_prime_UTR	Exon 1 of 1	NP_001119521.1
	PTEN	NM_000314.8	MANE Select	c.-1085C>T		upstream_gene	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.-565C>T		upstream_gene	N/A	NP_001291646.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-898G>A		5_prime_UTR	Exon 1 of 1	ENSP00000392204.2
	PTEN	ENST00000688308.1		c.-17+272C>T		intron	N/A	ENSP00000508752.1
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.-1085C>T		upstream_gene	N/A	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152148 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00446 AC: 884 AN: 198008 Hom.: 7 Cov.: 0 AF XY: 0.00475 AC XY: 476 AN XY: 100182

African (AFR) AF: 0.00141 AC: 8 AN: 5668

American (AMR) AF: 0.00275 AC: 15 AN: 5454

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 158 AN: 7270

East Asian (EAS) AF: 0.000596 AC: 11 AN: 18466

South Asian (SAS) AF: 0.0219 AC: 38 AN: 1732

European-Finnish (FIN) AF: 0.00194 AC: 46 AN: 23694

Middle Eastern (MID) AF: 0.0125 AC: 13 AN: 1040

European-Non Finnish (NFE) AF: 0.00424 AC: 517 AN: 122028

Other (OTH) AF: 0.00616 AC: 78 AN: 12656

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152260 Hom.: 4 Cov.: 32 AF XY: 0.00330 AC XY: 246 AN XY: 74454

African (AFR) AF: 0.00103 AC: 43 AN: 41572

American (AMR) AF: 0.00209 AC: 32 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.00484 AC: 25 AN: 5166

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 67984

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.0000542 Hom.: 0

Bravo AF: 0.00285

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	2	not specified (3)
-	-	3	PTEN hamartoma tumor syndrome (3)
-	-	1	Cowden syndrome 1 (1)
-	-	1	Cowden syndrome 4 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.0
DANN	Benign	0.86
PhyloP100		0.29
PromoterAI		0.040	Neutral
Mutation Taster		=295/5	polymorphism

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: rs538728843; hg19: chr10-89623142;