Submissions for variant NM_000455.5(STK11):c.829G>A (p.Asp277Asn)

dbSNP: rs1555738692

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001062281	SCV001227068	uncertain significance	Peutz-Jeghers syndrome	2023-07-27	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 856751). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the STK11 protein (p.Asp277Asn).
Color Diagnostics, LLC DBA Color Health	RCV001190034	SCV001357446	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 277 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Peutz-Jeghers syndrome in the literature but has been reported in an individual affected by breast cancer (PMID: 30287823). This variant has not been identified 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	RCV001062281	SCV002057850	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001062281	SCV002579550	uncertain significance	Peutz-Jeghers syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001190034	SCV002678329	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-03	criteria provided, single submitter	clinical testing	The p.D277N variant (also known as c.829G>A), located in coding exon 6 of the STK11 gene, results from a G to A substitution at nucleotide position 829. The aspartic acid at codon 277 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0.00014 in 7,051 unselected breast cancer patients and not present in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well 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.
GeneDx	RCV003324815	SCV004030737	uncertain significance	not provided	2023-08-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 15863673, 30287823)