Submissions for variant NM_000455.5(STK11):c.1071G>T (p.Glu357Asp)

gnomAD frequency: 0.00013  dbSNP: rs556651007

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082664	SCV000554124	likely benign	Peutz-Jeghers syndrome	2023-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571538	SCV000664355	benign	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000571538	SCV000910897	likely benign	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000833846	SCV000975610	likely benign	not provided	2018-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000833846	SCV002046355	benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001082664	SCV002057308	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268095	SCV002552031	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002268095	SCV004223355	likely benign	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1071G>T (p.Glu357Asp) results in a conservative amino acid change in 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 0.00013 in 245186 control chromosomes, predominantly at a frequency of 0.001 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 160 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The following publication has been ascertained in the context of this evaluation (PMID: 34326862). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=6) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV001082664	SCV004818977	likely benign	Peutz-Jeghers syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Institute of Medical Sciences, Banaras Hindu University	RCV001255638	SCV001432199	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356730	SCV001551976	likely benign	Familial ovarian cancer		no assertion criteria provided	clinical testing	The STK11 p.Glu357Asp variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors, databases. The variant was identified in dbSNP (ID: rs556651007) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae and uncertain significance by Ambry Genetics). The variant was identified in control databases in 30 of 242974 chromosomes (1 homozygous) at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 30 of 30492 chromosomes (freq: 0.00098), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Glu357 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.