ClinVar Miner

Submissions for variant NM_000455.5(STK11):c.542A>G (p.Asn181Ser)

dbSNP: rs886037859
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital RCV000241351 SCV000298003 likely pathogenic Peutz-Jeghers syndrome 2016-08-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492112 SCV000580896 pathogenic Hereditary cancer-predisposing syndrome 2020-12-24 criteria provided, single submitter clinical testing The p.N181S pathogenic mutation (also known as c.542A>G), located in coding exon 4 of the STK11 gene, results from an A to G substitution at nucleotide position 542. The asparagine at codon 181 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in two first-degree relatives from a family suspected of having Peutz-Jeghers syndrome (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the Mg-ATP binding in the active site of STK11 (Zeqiraj E et al. Science. 2009 Dec;326:1707-11; Gerlits O et al. Biochemistry. 2013 May;52:3721-7). Other alterations at the same codon (p.N181K, p.N181Y, p.N181T, p.N181E) have also been identified in individuals either diagnosed with or suspected to have Peutz-Jeghers syndrome (Ambry internal data; Ylikorkala A et al. Hum. Mol. Genet. 1999 Jan;8:45-51; Connolly DC et al. Am. J. Pathol. 2000 Jan;156:339-45; Amos CI et al. J. Med. Genet. 2004 May;41:327-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000241351 SCV000754014 pathogenic Peutz-Jeghers syndrome 2018-02-27 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to be de novo in an individual with features consistent with Peutz-Jeghers syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 254654). This sequence change replaces asparagine with serine at codon 181 of the STK11 protein (p.Asn181Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine.
Color Diagnostics, LLC DBA Color Health RCV000492112 SCV000905234 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-06 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 181 in the active site of the kinase domain of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported by an external laboratory to be de novo in an individual with features consistent with Peutz-Jeghers syndrome (Clinvar variation ID: 254654). Multiple different amino acid substitutions occurring at this position, p.Asn181Lys, p.Asn181Glu, p.Asn181Thr, p.Asn181Ile, have been reported in individuals affected with Peutz-Jeghers syndrome, indicating that asparagine at this position is important for STK11 protein function (PMID: 9887330, 15863673, 30689838; Clinvar variation ID: 428757). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Genome-Nilou Lab RCV000241351 SCV002057365 likely pathogenic Peutz-Jeghers syndrome 2021-07-15 criteria provided, single submitter clinical testing

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