rs730881979

Variant names:

• chr19-1220434-G-A
• rs730881979
• NM_000455.5:c.526G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1220434-G-A
• chr19-1220434-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.526G>A​(p.Asp176Asn) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.86
• Publications: 14 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220434-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3963258.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 19-1220434-G-A is Pathogenic according to our data. Variant chr19-1220434-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 182907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.526G>A	p.Asp176Asn	missense_variant	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.526G>A	p.Asp176Asn	missense_variant	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1	n.1793G>A		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.526G>A	p.Asp176Asn	missense_variant	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.526G>A	p.Asp176Asn	missense_variant	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.154G>A	p.Asp52Asn	missense_variant	Exon 6 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*351G>A		non_coding_transcript_exon_variant	Exon 5 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*351G>A		3_prime_UTR_variant	Exon 5 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236468 AF XY: 0.00000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000108 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 176 of the STK11 protein (p.Asp176Asn). 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 individuals with Peutz-Jeghers syndrome (PJS) (PMID: 9399902, 9837816, 17924967, 24604241, 24652667). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182907). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. Experimental studies have shown that this missense change affects STK11 function (PMID: 9837816, 10441497, 15987703). For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 16, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D176N pathogenic mutation (also known as c.526G>A), located in coding exon 4 of the STK11 gene, results from a G to A substitution at nucleotide position 526. The aspartic acid at codon 176 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several individuals affected with Peutz-Jeghers syndrome (de Leng WW et al. Clin. Genet., 2007 Dec;72:568-73; Yang HR et al. Dig. Dis. Sci., 2010 Dec;55:3458-65; Wang Z et al. Hum. Mutat., 2014 Jul;35:851-8; Dai L et al. Dig. Dis. Sci., 2014 Aug;59:1856-61; Chiang JM et al. Asian J Surg, 2018 Sep;41:480-485), and has been shown to segregate with disease in one family (Mehenni H et al. Am. J. Hum. Genet., 1997 Dec;61:1327-34). Functional studies of this alteration have also demonstrated severely reduced autophosphorylation compared to wild type STK11 in an in vitro protein kinase assay. This alteration also demonstrated subcellular localization similar to wildtype and maintained interaction with PTEN (Mehenni H et al. Am. J. Hum. Genet., 1998 Dec;63:1641-50; Mehenni H et al. Hum. Mol. Genet., 2005 Aug;14:2209-19). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	.;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		1.0
MutPred		0.96		Loss of catalytic residue at D176 (P = 0.0452);Loss of catalytic residue at D176 (P = 0.0452);.;
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730881979; hg19: chr19-1220433; COSMIC: COSV58825680; COSMIC: COSV58825680;