rs906049559

Positions:

• chr19-1206920-G-A
• chr19-1206920-G-C
• chr19-1206920-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000455.5(STK11):​c.7G>A​(p.Val3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08239201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.7G>A	p.Val3Met	missense_variant	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.7G>A	p.Val3Met	missense_variant	1/9		NP_001394184.1
STK11	NR_176325.1	n.1143G>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.7G>A	p.Val3Met	missense_variant	1/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429464 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708260

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2023	The p.V3M variant (also known as c.7G>A), located in coding exon 1 of the STK11 gene, results from a G to A substitution at nucleotide position 7. The valine at codon 3 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Peutz-Jeghers syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 3 of the STK11 protein (p.Val3Met). 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: 419872). 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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in patients with breast cancer but also in unaffected controls (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991) -

Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.36	.;N;.
REVEL	Benign	0.052
Sift	Benign	0.086	.;T;.
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.053
MutPred		0.22		Loss of catalytic residue at M1 (P = 0.0379);Loss of catalytic residue at M1 (P = 0.0379);Loss of catalytic residue at M1 (P = 0.0379);
MVP		0.30
MPC		0.99
ClinPred		0.11	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.59

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: rs906049559; hg19: chr19-1206919;