19-1220641-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000455.5(STK11):c.658C>T(p.Gln220*) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q220Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.80

Publications

16 publications found

Variant links:

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

STK11 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-1220641-C-T is Pathogenic according to our data. Variant chr19-1220641-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 428776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.658C>T	p.Gln220*	stop_gained	Exon 5 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.658C>T	p.Gln220*	stop_gained	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1925C>T		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.658C>T	p.Gln220*	stop_gained	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.658C>T	p.Gln220*	stop_gained	Exon 5 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.286C>T	p.Gln96*	stop_gained	Exon 7 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*483C>T		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*483C>T		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724154

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

44306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

85826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110042

Other (OTH)

AF:

0.00

AC:

AN:

60082

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Pathogenic:6

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The following ACMG criteria was used: PVS1; PM2_SUP; PS4_SUP -

Dec 05, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln220*) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with lung adenocarcinomas and Peutz-Jeghers syndrome (PMID: 9850045, 9887330, 20559149, 23515270, 26979979). This variant is also known as c.2681C>T. ClinVar contains an entry for this variant (Variation ID: 428776). For these reasons, this variant has been classified as Pathogenic. -

Feb 12, 2024

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Jul 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.658C>T (p.Q220*) variant in STK11 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant has been reported in multiple affected individuals and was shown to segregate with the disease in at least one family (Yajima, 2013). The variant is absent from ExAC (~85428 chrs tested). Taken together, the variant was classified as Pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 12, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Identified in patients with Peutz-Jeghers syndrome in published literature (Gruber 1998, Kruse 1999, Huang 2015); This variant is associated with the following publications: (PMID: 15188174, 16287113, 10090485, 26607058, 20559149, 17026623, 26979979, 9887330, 23515270, 28560011, 9850045, 28724667, 23415580, 16707622) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Aug 25, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q220* pathogenic mutation (also known as c.658C>T), located in coding exon 5 of the STK11 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been seen in multiple patients and families with Peutz-Jeghers syndrome (Chow E et al. Clin Genet. 2006 Nov;70(5):409-14; Aretz S et al. Hum Mutat. 2005 Dec;26(6):513-9; Gruber S et al. Cancer Res. 1998 Dec 1;58(23):5267-70; Zhang LJ et al. Am J Transl Res. 2017 May;9(5):2639-2644). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.94

PhyloP100

7.8

Vest4

0.94

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over