rs765890997

Positions:

• chr19-1218426-A-C
• chr19-1218426-A-G
• chr19-1218426-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000455.5(STK11):​c.300A>C​(p.Gln100His) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.96

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.300A>C	p.Gln100His	missense_variant	2/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.300A>C	p.Gln100His	missense_variant	2/9		NP_001394184.1
STK11	NR_176325.1	n.1567A>C		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.300A>C	p.Gln100His	missense_variant	2/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.300A>C	p.Gln100His	missense_variant	2/9			ENSP00000498804.1
STK11	ENST00000585748	c.-73A>C		5_prime_UTR_variant	4/12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*125A>C		non_coding_transcript_exon_variant	3/4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*125A>C		3_prime_UTR_variant	3/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 565978). 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 glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 100 of the STK11 protein (p.Gln100His). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The p.Q100H variant (also known as c.300A>C), located in coding exon 2 of the STK11 gene, results from an A to C substitution at nucleotide position 300. The glutamine at codon 100 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Benign	0.66
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Uncertain	0.35
Sift	Benign	0.12	.;T
Sift4G	Benign	0.21	T;T
Polyphen		0.037	.;B
Vest4		0.80
MutPred		0.49		Gain of catalytic residue at L102 (P = 0.1404);Gain of catalytic residue at L102 (P = 0.1404);
MVP		0.89
MPC		2.1
ClinPred		0.23	T
GERP RS		-2.5
Varity_R		0.42
gMVP		0.62

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: rs765890997; hg19: chr19-1218425;