STK11 c.1249G>T, p.Ala417Ser
NM_000455.5:c.1249G>T
Variant of Uncertain Significance (VUS)
The variant c.1249G>T (p.A417S) in STK11 is a missense change with extremely low population frequency (PM2 moderate) but strong functional evidence for no impact (BS3 strong) and multiple benign supporting criteria (BP1, BP4). No pathogenic supporting criteria are met; however, conflicting moderate pathogenic evidence and strong benign evidence yield classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BS3
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
STK11
Transcript
NM_000455.5
MANE Select
Total Exons
10
Strand
Forward (+)
Reference Sequence
NC_000019.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000455.4 | RefSeq Select | 10 exons | Forward |
Variant Details
HGVS Notation
NM_000455.5:c.1249G>T
Protein Change
A417S
Location
Exon 9
(Exon 9 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 417 in gene STK11
Variant interpretation based on transcript NM_000455.5
Genome Browser
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HGVS InputNM_000455:c.1249G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0012%
Rare
Highest in Population
Remaining individuals
0.0219%
Low Frequency
Global: 0.0012%
Remaining individuals: 0.0219%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 166156Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0012%, 2/166156 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0219%, 1/4566 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
8 VUS
1 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This missense variant replaces alanine with serine at codon 417 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant did not impact autophosphorylation activity (PMID: 34849607). This variant has been reported in an individual affected with Peutz-Jeghers syndrome in the literature (http://www.pifukezazhi.com/EN/Y2014/V47/I10/744). This variant has been identified in 2/166156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This missense variant replaces alanine with serine at codon 417 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant did not impact autophosphorylation activity (PMID: 34849607). This variant has been reported in an individual affected with Peutz-Jeghers syndrome in the literature ( http://www.pifukezazhi.com/EN/Y2014/V47/I10/744 ). This variant has been identified in 2/166156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Likely benign (1 clinical laboratories) and as Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 417 in gene STK11
Functional Summary
The STK11 A417S variant has been functionally characterized and is likely neutral. In vitro studies demonstrate that this variant exhibits kinase activity and TP53-mediated transcriptional activity comparable to the wild-type protein, indicating no significant impact on STK11 protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.64
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism.' The evidence for this variant shows: it is a missense change (A417S), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no known pathogenic variant at amino acid position 417. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo data are provided. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: in vitro functional studies demonstrate wild-type kinase and TP53-mediated activity, indicating no damaging effect. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: no case-control or patient prevalence data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: position 417 is not established as a mutational hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: MAF = 0.0012% in gnomAD with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders).' The evidence for this variant shows: STK11‐related disease is autosomal dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: it is a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen.' The evidence for this variant shows: no other pathogenic missense changes reported at residue 417. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo or family data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: STK11 disease mechanism is primarily loss of function, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: in silico predictors are mixed, CADD=2.64, SpliceAI=0.01, supporting benign. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no detailed phenotype provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: no reputable source reports pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for disorder.' The evidence for this variant shows: MAF = 0.0012%, far below BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: frequency is very low, not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age.' The evidence for this variant shows: no healthy adult carrier data. Therefore, this criterion is not applied.
BS3
BS3 (Strong)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: in vitro studies demonstrate normal kinase and TP53-mediated activity. Therefore, this criterion is applied at Strong strength because functional assays indicate no impact.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease.' The evidence for this variant shows: STK11 disease mechanism is haploinsufficiency (loss of function), and this is a missense variant. Therefore, this criterion is applied at Supporting strength because missense is an unlikely mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact.' The evidence for this variant shows: CADD=2.64, SpliceAI=0.01, mixed but overall benign predictions. Therefore, this criterion is applied at Supporting strength because in silico tools predict no effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence.' The evidence for this variant shows: ClinVar contains a single benign assertion, but overall conflicting. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: it is missense, not synonymous. Therefore, this criterion is not applied.