rs376329042

Positions:

• chr19-1223009-G-A
• chr19-1223009-G-C
• chr19-1223009-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000455.5(STK11):​c.945G>A​(p.Pro315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,571,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P315P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (1 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -0.512

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-1223009-G-A is Benign according to our data. Variant chr19-1223009-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1223009-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.512 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000624 (95/152314) while in subpopulation AMR AF= 0.0017 (26/15302). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.945G>A	p.Pro315=	synonymous_variant	8/10	ENST00000326873.12
STK11	NM_001407255.1	c.945G>A	p.Pro315=	synonymous_variant	8/9
STK11	NR_176325.1	n.2212G>A		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.945G>A	p.Pro315=	synonymous_variant	8/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000789 AC: 151 AN: 191344 Hom.: 0 AF XY: 0.000725 AC XY: 75 AN XY: 103392

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000352

Gnomad ASJ exome AF: 0.00617

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000675

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.000764

Gnomad OTH exome AF: 0.000402

GnomAD4 exome AF: 0.000951 AC: 1350 AN: 1419262 Hom.: 1 Cov.: 31 AF XY: 0.000922 AC XY: 647 AN XY: 701450

Gnomad4 AFR exome AF: 0.000308

Gnomad4 AMR exome AF: 0.000383

Gnomad4 ASJ exome AF: 0.00492

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.000934

Gnomad4 FIN exome AF: 0.000182

Gnomad4 NFE exome AF: 0.000964

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74468

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000906 Hom.: 0

Bravo AF: 0.000699

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	STK11: BP4, BP7 -

Peutz-Jeghers syndrome Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2013	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. -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 04, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2014	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. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 05, 2023

- -

STK11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

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

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Pro315= variant was identified in 2 of 144 proband chromosomes (frequency: 0.01) from Spanish and Australian individuals or families with Lynch syndrome or PJS (Peutz–Jeghers syndrome (Vargas-Parra_2017_28577310, Scott_2002_12372054 ). The variant was also identified in dbSNP (ID: rs376329042) “With Likely benign allele”, ClinVar (classified benign by Invitae, GeneDx, and Quest Diagnostics Nichols Institute San Juan Capistrano, and likely benign by Ambry Genetics), Clinvitae (3x), Cosmic (1x in a carcinoma of the large intestine), Zhejiang Colon Cancer Database (8x), and in control databases in 150 of 218304 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 19118 chromosomes (freq: 0.0002), Other in 3 of 5448 chromosomes (freq: 0.0006), Latino in 10 of 28572 chromosomes (freq: 0.0004), European Non-Finnish in 66 of 95490 chromosomes (freq: 0.0007), Ashkenazi Jewish in 48 of 8990 chromosomes (freq: 0.005), European Finnish in 2 of 20554 chromosomes (freq: 0.0001), and South Asian in 18 of 25328 chromosomes (freq: 0.0007) while not observed in the East Asian population. The variant was not identified in MutDB, LOVD 3.0, and Insight Hereditary Tumors Database The p.Pro315= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.97
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs376329042; hg19: chr19-1223008; COSMIC: COSV58826952; COSMIC: COSV58826952;