chr19-1220641-C-T

Position:

• chr19-1220641-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.80

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 428776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.658C>T	p.Gln220*	stop_gained	5/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.658C>T	p.Gln220*	stop_gained	5/9		NP_001394184.1
STK11	NR_176325.1	n.1925C>T		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.658C>T	p.Gln220*	stop_gained	5/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.658C>T	p.Gln220*	stop_gained	5/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.286C>T	p.Gln96*	stop_gained	7/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 12, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428776). This variant is also known as c.2681C>T. 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 not present in population databases (gnomAD no frequency). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2016	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2018

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	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.94
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1131690940; hg19: chr19-1220640; COSMIC: COSV58820792; COSMIC: COSV58820792;