chr19-1223136-G-T

Variant names:

• chr19-1223136-G-T
• rs587778696
• NM_000455.5:c.1072G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000455.5(STK11):​c.1072G>T​(p.Asp358Tyr) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D358N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.1072G>T	p.Asp358Tyr	missense_variant	Exon 8 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.1072G>T	p.Asp358Tyr	missense_variant	Exon 8 of 9		NP_001394184.1
STK11	NR_176325.1	n.2339G>T		non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1072G>T	p.Asp358Tyr	missense_variant	Exon 8 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.1072G>T	p.Asp358Tyr	missense_variant	Exon 8 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.700G>T	p.Asp234Tyr	missense_variant	Exon 10 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*897G>T		non_coding_transcript_exon_variant	Exon 9 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*897G>T		3_prime_UTR_variant	Exon 9 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D358Y variant (also known as c.1072G>T), located in coding exon 8 of the STK11 gene, results from a G to T substitution at nucleotide position 1072. The aspartic acid at codon 358 is replaced by tyrosine, an amino acid with highly dissimilar 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	2.0	.;M
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.012	.;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	.;D
Vest4		0.62
MutPred		0.49		Gain of phosphorylation at D358 (P = 0.0222);Gain of phosphorylation at D358 (P = 0.0222);
MVP		0.82
MPC		0.29
ClinPred		0.96	D
GERP RS		2.7
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.69
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587778696; hg19: chr19-1223135;