19-1222987-G-T

Variant names:

• chr19-1222987-G-T
• rs864622488
• NM_000455.5:c.923G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.923G>T​(p.Trp308Leu) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W308C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1222988-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2736757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 19-1222987-G-T is Pathogenic according to our data. Variant chr19-1222987-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220351.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	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 9		NP_001394184.1
STK11	NR_176325.1	n.2190G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.551G>T	p.Trp184Leu	missense_variant, splice_region_variant	Exon 10 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C2931038:Familial pancreatic carcinoma Pathogenic:1

Nov 07, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peutz-Jeghers syndrome Pathogenic:1

Sep 24, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with leucine at codon 308 of the STK11 protein (p.Trp308Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine. For these reasons, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature as a germline variant. Three different missense substitutions at this codon (p.Trp308Cys, p.Trp308Gly, p.Trp308Ser),  one of which abolished STK11 kinase activity in vitro (PMID: 9837816), have been reported in patients affected with Peutz–Jeghers syndrome (PMID: 9837816, 24604241, 23415580). These observations suggest that this novel missense substitution at the Trp308 residue may affect protein function, but experiments have not been done to test this possibility. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-12	.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.87		Gain of catalytic residue at W308 (P = 0.0072);Gain of catalytic residue at W308 (P = 0.0072);
MVP		0.70
MPC		0.37
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.89

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: rs864622488; hg19: chr19-1222986; COSMIC: COSV58822407; COSMIC: COSV58822407;