19-1219412-G-T

Position:

• chr19-1219412-G-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.463G>T​(p.Gly155Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,429,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: STK11 NM_000455.5 missense, splice_region
• Scores: Splicing: ADA: 0.4614
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 9.70

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 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, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.463G>T	p.Gly155Trp	missense_variant, splice_region_variant	3/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.463G>T	p.Gly155Trp	missense_variant, splice_region_variant	3/9		NP_001394184.1
STK11	NR_176325.1	n.1730G>T		splice_region_variant, non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.463G>T	p.Gly155Trp	missense_variant, splice_region_variant	3/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.463G>T	p.Gly155Trp	missense_variant, splice_region_variant	3/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.91G>T	p.Gly31Trp	missense_variant, splice_region_variant	5/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000153 AC: 3 AN: 196374 Hom.: 0 AF XY: 0.0000189 AC XY: 2 AN XY: 105892

Gnomad AFR exome AF: 0.0000900

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000398

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429942 Hom.: 0 Cov.: 52 AF XY: 0.00000282 AC XY: 2 AN XY: 708332

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: 0.0000367

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000254 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces glycine with tryptophan at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 been identified in 3/196374 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2023	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 527835). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 155 of the STK11 protein (p.Gly155Trp). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Mar 15, 2022	A heterozygous missense variation in exon 3 of the STK11 gene that results in the amino acid substitution of Tryptophan for Glycine at codon 155 was detected. The variant has previously been reported in breast and/or ovarian cancer patients [PMID: 29470806]. It lies in the protein kinase domain of the STK11_HUMAN protein. The observed variant c.155G>T (p.Gly155Trp) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2024	The p.G155W variant (also known as c.463G>T), located in coding exon 3 of the STK11 gene, results from a G to T substitution at nucleotide position 463. The glycine at codon 155 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 27, 2023	This missense variant replaces glycine with tryptophan at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been in two individual from a cohort affected with breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 3/196374 chromosomes 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	.;D
REVEL	Uncertain	0.53
Sift	Benign	0.11	.;T
Sift4G	Benign	0.18	T;T
Polyphen		1.0	.;D
Vest4		0.85
MVP		0.33
MPC		1.3
ClinPred		0.65	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.010		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: rs763353991; hg19: chr19-1219411;