19-1223172-G-A

Position:

• chr19-1223172-G-A

Variant summary

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

The NM_000455.5(STK11):​c.1108G>A​(p.Gly370Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,458 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: STK11 NM_000455.5 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 9.21

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.1108G>A	p.Gly370Arg	missense_variant, splice_region_variant	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.1108G>A	p.Gly370Ser	missense_variant, splice_region_variant	8/9		NP_001394184.1
STK11	NR_176325.1	n.2375G>A		splice_region_variant, non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1108G>A	p.Gly370Arg	missense_variant, splice_region_variant	8/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.1108G>A	p.Gly370Ser	missense_variant, splice_region_variant	8/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.736G>A	p.Gly246Arg	missense_variant, splice_region_variant	10/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457458 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 10, 2023	This missense variant replaces glycine with arginine at codon 370 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. In a case-control study conducted in Japan, this variant was reported in 1/7051 female breast cancer cases and absent in 11241 controls (PMID: 30287823). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 370 of the STK11 protein (p.Gly370Arg). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. 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. This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 185965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	Aug 12, 2024	The p.G370R variant (also known as c.1108G>A), located in coding exon 8 of the STK11 gene, results from a G to A substitution at nucleotide position 1108. The glycine at codon 370 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 8 and may have some effect on normal mRNA splicing. This variant has been reported in 1 in 7051 unselected breast cancer patients and 0 of 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This nucleotide position is highly conserved on sequence alignment. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces glycine with arginine at codon 370 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. In a case-control study conducted in Japan, this variant was reported in 1/7051 female breast cancer cases and absent in 11241 controls (PMID: 30287823). 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.14	.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	.;D
Sift4G	Benign	0.46	T;T
Polyphen		0.97	.;D
Vest4		0.76
MutPred		0.32		Gain of phosphorylation at T367 (P = 0.0921);Gain of phosphorylation at T367 (P = 0.0921);
MVP		0.70
MPC		0.12
ClinPred		0.81	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.020		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: rs747655835; hg19: chr19-1223171;