rs786201090

chr19-1221996-C-Gchr19-1221996-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000455.5(STK11):c.910C>G(p.Arg304Gly) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.219

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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 chr19-1221997-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 19-1221996-C-G is Pathogenic according to our data. Variant chr19-1221996-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2859361.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.910C>G	p.Arg304Gly	missense_variant	7/10	ENST00000326873.12
STK11	NM_001407255.1	c.910C>G	p.Arg304Gly	missense_variant	7/9
STK11	NR_176325.1	n.2177C>G		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.910C>G	p.Arg304Gly	missense_variant	7/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 12, 2023

This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 304 of the STK11 protein (p.Arg304Gly). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg304 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9809980, 10441497, 12552571, 12865922, 15121768, 16287113, 17404884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;D
Eigen	Benign	0.11
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.72		Loss of catalytic residue at R304 (P = 0.0048);Loss of catalytic residue at R304 (P = 0.0048);
MVP		0.94
MPC		0.32
ClinPred		0.94	D
GERP RS		-2.3
Varity_R		0.95
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1221995; COSMIC: COSV58822715; COSMIC: COSV58822715;