rs537906142

chr19-1223105-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000455.5(STK11):c.1041G>A(p.Ala347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,611,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A347A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.978

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 19-1223105-G-A is Benign according to our data. Variant chr19-1223105-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184691.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=4, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.978 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000394 (6/152264) while in subpopulation SAS AF= 0.00125 (6/4816). AF 95% confidence interval is 0.000542. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.1041G>A	p.Ala347=	synonymous_variant	8/10	ENST00000326873.12
STK11	NM_001407255.1	c.1041G>A	p.Ala347=	synonymous_variant	8/9
STK11	NR_176325.1	n.2308G>A		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.1041G>A	p.Ala347=	synonymous_variant	8/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 30 AN: 243790 Hom.: 0 AF XY: 0.000173 AC XY: 23 AN XY: 132860

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 SAS exome AF: 0.000930

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000754 AC: 110 AN: 1458986 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 725578

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000567 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 12, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 06, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2017	Variant summary: The STK11 c.1041G>A (p.Ala347Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant changes in ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. Although the variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004), these studies provided no functional evidence to that effect and this report predated the development of large scale control population databases. The variant was found in the large control database ExAC in 17 of 95258 control chromosomes from all ethnicities, but was predominantly observed in the South Asian subpopulation at a frequency of 0.001139 (15/13164). This frequency is about 73 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000156), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. Multiple clinical diagnostic laboratories have classified this variant with conflicting interpretations, including uncertain significance (1x in ClinVar), likely benign (1x in ClinVar), and benign (1x in ClinVar). Taken together, this variant is classified as benign. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2015

This variant is denoted STK11 c.1041G>A at the DNA level. Although the variant is silent at the coding level, preserving an Alanine at codon 347, this variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004); however, splicing models at our laboratory do not predict an effect on splicing. STK11 c.1041G>A was not observed at a significant allele frequency in 1000 Genomes. The nucleotide which is altered, a guanine (G) at base 1041, is not conserved across species. Based on currently available information, it is unclear whether STK11 c.1041G>A is pathogenic or benign. We consider this to be a variant of uncertain significance. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Ala347Ala variant was identified in 1 of 84 proband chromosomes (frequency: 0.01) from individuals or families with Peutz-Jaghers Syndrome (Amos 2004). The variant was identified in dbSNP (rs537906142) as “with likely benign, uncertain significance allele”, in ClinVar (interpreted as "benign" by Invitae and 2 others, "likely benign" by Ambry Genetics and "uncertain significance" by GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 27 of 241,514 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant as this frequency is well above the known prevalence of Peutz-Jagher Syndrome (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 109,548 chromosomes (freq: 0.000009), Finnish in 1 of 21,340 chromosomes (freq: 0.00005), and South Asian in 25 of 30,278 chromosomes (freq: 0.0008). The variant was not observed in the African, Other, Latino, Ashkenazi Jewish, or East Asian populations. The p.Ala347= 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted the creation of a new splice site. 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. -

STK11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.2
Dann	Benign	0.84

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: rs537906142; hg19: chr19-1223104; COSMIC: COSV58826093; COSMIC: COSV58826093;