rs549474196

Positions:

• chr19-1223034-C-G
• chr19-1223034-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000455.5(STK11):​c.970C>G​(p.Pro324Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000054 in 1,593,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (1 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:11
• Conservation: PhyloP100: 5.80

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019876808).
• BP6: Variant 19-1223034-C-G is Benign according to our data. Variant chr19-1223034-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127710.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=4, Benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000361 (55/152264) while in subpopulation AMR AF= 0.00333 (51/15302). AF 95% confidence interval is 0.0026. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.970C>G	p.Pro324Ala	missense_variant	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.970C>G	p.Pro324Ala	missense_variant	8/9		NP_001394184.1
STK11	NR_176325.1	n.2237C>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.970C>G	p.Pro324Ala	missense_variant	8/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.970C>G	p.Pro324Ala	missense_variant	8/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.598C>G	p.Pro200Ala	missense_variant	10/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000507 AC: 11 AN: 216848 Hom.: 0 AF XY: 0.0000509 AC XY: 6 AN XY: 117988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.000551

GnomAD4 exome AF: 0.0000215 AC: 31 AN: 1441686 Hom.: 1 Cov.: 31 AF XY: 0.0000182 AC XY: 13 AN XY: 715350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000573

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: 0.00

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.000793

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 12, 2022	The STK11 c.970C>G (p.Pro324Ala) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in individuals undergoing testing for hereditary cancer predisposition (PMID: 25117502, 25980754). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 21, 2015	- -

not specified Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2020	DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.970C>G, in exon 8 that results in an amino acid change, p.Pro324Ala. This sequence change does not appear to have been previously described in patients with STK11-related disorders and has been described in the gnomAD database with a low population frequency of 0.0048% (dbSNP rs549474196). The p.Pro324Ala change affects a highly conserved amino acid residue located in a domain of the STK11 protein that is not known to be functional. The p.Pro324Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro324Ala change remains unknown at this time. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2021	Variant summary: STK11 c.970C>G (p.Pro324Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 150920 control chromosomes, predominantly at a frequency of 0.0033 within the Latino subpopulation in the gnomAD database (v3.1 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 500-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.970C>G has been reported in the literature in individuals undergoing clinical genetic testing for hereditary cancer risk assessment (Selkirk_2014, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=4) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 04, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 22, 2021	- -

STK11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.35	T;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.0	.;D
REVEL	Benign	0.28
Sift	Benign	0.16	.;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0060	.;B
Vest4		0.32
MutPred		0.41		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.65
MPC		0.044
ClinPred		0.070	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs549474196; hg19: chr19-1223033;