rs587782032

chr19-1220467-G-Achr19-1220467-G-Cchr19-1220467-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1 PM5 BP4_Moderate BP6 BS2

The NM_000455.5(STK11):c.559G>A(p.Gly187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,606,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. G187C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 0.532

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000455.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220466-CGG-CT is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10190928).
• BP6: Variant 19-1220467-G-A is Benign according to our data. Variant chr19-1220467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141815.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5}.
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.559G>A	p.Gly187Ser	missense_variant	4/10	ENST00000326873.12
STK11	NM_001407255.1	c.559G>A	p.Gly187Ser	missense_variant	4/9
STK11	NR_176325.1	n.1826G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.559G>A	p.Gly187Ser	missense_variant	4/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000339 AC: 8 AN: 236080 Hom.: 0 AF XY: 0.0000389 AC XY: 5 AN XY: 128484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000578

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000469

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.0000392 AC: 57 AN: 1454774 Hom.: 0 Cov.: 32 AF XY: 0.0000470 AC XY: 34 AN XY: 723048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000442

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000333 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2019	Variant summary: STK11 c.559G>A (p.Gly187Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR039154) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284338 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome (PJS) phenotype (6.3e-06), strongly suggesting that the variant is benign. Though the variant, c.559G>A, has been reported in the literature in individuals affected with lung-, and breast cancer (Kim_2010, Couch_2015, Momozawa_ 2018), in one of these cases it was noted that the affected patient did not have any clinical manifestations of PJS (Kim_2010); moreover the variant was also reported in multiple healthy controls (Kim_2010, Momozawa_ 2018 and in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2022	DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.559G>A, in exon 4 that results in an amino acid change, p.Gly187Ser. This sequence has been previously described in individuals with breast cancer, small cell lung cancers (NSCLC) and has also been described in control population (PMIDs: 25452441, 30287823, 20082862 and FLOSSIES database). This sequence change has been described in the gnomAD database in eight individuals which corresponds to a population frequency of 0.003% (dbSNP rs587782032). The p.Gly187Ser change affects a poorly conserved amino acid residue located in a domain of the STK11 protein that is known to be functional. The p.Gly187Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly187Ser change remains unknown at this time. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2017	This variant is denoted STK11 c.559G>A at the cDNA level, p.Gly187Ser (G187S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant was observed in at least one individual with triple negative breast cancer (Couch 2015). STK11 Gly187Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly187Ser occurs at a position that is not conserved and is located in the protein kinase domain and in the region required for binding of substrate and initiation of phospho transfer (UniProt, Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Gly187Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 17, 2019	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Gly187Ser variant was identified in 3 of 10699 proband chromosomes (frequency: 0.0003) from triple negative BRCA families and Japanese women with breast cancer and was present in 2 of 11241 control chromosomes (frequency: 0.00018) from healthy individuals (Couch 2015, Momozawa 20118). The variant was also identified in dbSNP (ID: rs587782032) as “With Uncertain significance allele”, ClinVar (5x as uncertain significance and 1x as likely benign by Ambry Genetics, Invitae, GeneDx, Integrated Genetics, Counsyl, Mendelics) and LOVD 3.0 (4x as uncertain significance). The variant was identified in control databases in 7 of 233812 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5256 chromosomes (freq: 0.0002), European Non-Finnish in 5 of 105720 chromosomes (freq: 0.00005) and East Asian in 1 of 16594 chromosomes (freq: 0.00006), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish or South Asian populations. The p.Gly187 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.36
Dann	Benign	0.82
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.85	T;D;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.23
MVP		0.52
MPC		0.97
ClinPred		0.032	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.080
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782032; hg19: chr19-1220466; COSMIC: COSV58827697; COSMIC: COSV58827697;