19-1219409-C-G

Variant names:

• chr19-1219409-C-G
• rs878853988
• NM_000455.5:c.460C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000455.5(STK11):​c.460C>G​(p.His154Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H154Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.67
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 40 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 19-1219409-C-G is Pathogenic according to our data. Variant chr19-1219409-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237801.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.460C>G	p.His154Asp	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.460C>G	p.His154Asp	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1727C>G		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.460C>G	p.His154Asp	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.460C>G	p.His154Asp	missense_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.88C>G	p.His30Asp	missense_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*285C>G		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*285C>G		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

May 04, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H154D variant (also known as c.460C>G), located in coding exon 3 of the STK11 gene, results from a C to G substitution at nucleotide position 460. The histidine at codon 154 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with Peutz-Jeghers syndrome (Zhao X et al. Nan Fang Yi Ke Da Xue Xue Bao, 2012 Apr;32:511-4; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Peutz-Jeghers syndrome Uncertain:1

Mar 02, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with aspartic acid at codon 154 of the STK11 protein (p.His154Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant has been reported in an individual affected with Peutz-Jeghers syndrome (PMID: 22543132). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.82	.;L
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.4	.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.012	.;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.65		Loss of catalytic residue at G155 (P = 0.0878);Loss of catalytic residue at G155 (P = 0.0878);
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs878853988; hg19: chr19-1219408; COSMIC: COSV58829856; COSMIC: COSV58829856;