Submissions for variant NM_000455.5(STK11):c.355A>G (p.Asn119Asp)

gnomAD frequency: 0.00004  dbSNP: rs545015076

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205670	SCV000259324	likely benign	Peutz-Jeghers syndrome	2023-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564055	SCV000664359	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-19	criteria provided, single submitter	clinical testing	The p.N119D variant (also known as c.355A>G), located in coding exon 2 of the STK11 gene, results from an A to G substitution at nucleotide position 355. The asparagine at codon 119 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564055	SCV000686636	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 119 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 11/249110 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.
Genome-Nilou Lab	RCV000205670	SCV002057776	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564055	SCV002531684	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491952	SCV004239720	uncertain significance	Breast and/or ovarian cancer	2023-04-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000205670	SCV004816346	uncertain significance	Peutz-Jeghers syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 119 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 11/249110 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356672	SCV001551907	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Asn119Asp variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (rs545015076) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Color). The variant was identified in control databases in 11 of 249,110 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 10 of 30,600 chromosomes (freq: 0.0003, decreasing the likelihood that this variant has clinical significance) and Other in 1 of 6048 chromosomes (freq: 0.0002), but it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish or European populations. The p.Asn119 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.