rs1064793938

chr19-1226627-T-Achr19-1226627-T-Cchr19-1226627-T-G

Variant summary

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

The NM_000455.5(STK11):c.1282T>A(p.Ser428Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000359 in 1,391,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S428L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.1282T>A	p.Ser428Thr	missense_variant	9/10	ENST00000326873.12
STK11	NR_176325.1	n.2549T>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.1282T>A	p.Ser428Thr	missense_variant	9/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1391494 Hom.: 0 Cov.: 31 AF XY: 0.00000437 AC XY: 3 AN XY: 686146

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: 0.00000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 428 of the STK11 protein (p.Ser428Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 419536). 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 not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2022	The p.S428T variant (also known as c.1282T>A), located in coding exon 9 of the STK11 gene, results from a T to A substitution at nucleotide position 1282. The serine at codon 428 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 12, 2022	This missense variant replaces serine with threonine at codon 428 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 25, 2019

Variant summary: STK11 c.1282T>A (p.Ser428Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 140794 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1282T>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (RAD51C c.1282T>A, p.Tyr210X). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18854309, 18321849, 28900777) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0088	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.30	T;T
Polyphen		0.98	.;D
Vest4		0.55
MutPred		0.25		.;Gain of helix (P = 0.062);
MVP		0.67
MPC		0.13
ClinPred		0.80	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.30

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: rs1064793938; hg19: chr19-1226626;