Submissions for variant NM_000455.5(STK11):c.1257C>T (p.Ser419=)

gnomAD frequency: 0.00006  dbSNP: rs375328708

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213040	SCV000211693	benign	not specified	2014-08-19	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.
Ambry Genetics	RCV000160983	SCV000213576	likely benign	Hereditary cancer-predisposing syndrome	2015-06-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083993	SCV000554141	likely benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160983	SCV000691482	likely benign	Hereditary cancer-predisposing syndrome	2017-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589957	SCV000696710	benign	not provided	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.1257C>T (p.Ser419Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 4/21878 control chromosomes at a frequency of 0.0001828, which is approximately 29 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. This variant is co-occuring with a pathogenic variant MSH2 c.366+1G>A in an internal specimen. Taken together, this variant is classified as benign.
Genome-Nilou Lab	RCV001083993	SCV002057701	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160983	SCV002531667	benign	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589957	SCV001554323	likely benign	not provided		no assertion criteria provided	clinical testing	The STK11 p.Ser419= variant was identified in the literature in 11241 female controls with frequency 0.00009 and was not identified in 12490 male controls and 53 male or 7051 female breast cancer cases (Momozawa 2018). The variant was also identified in dbSNP (ID: rs375328708) as "With Likely benign allele", ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Ambry Genetics and Color), and LOVD 3.0 (1x as benign) . The variant was also identified with co-occuring pathogenic variant (MSH2 c.366+1G>A) in an internal specimen in Integrated Genetics/Laboratory Corporation of America. The variant was identified in control databases in 13 of 189044 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 16152 chromosomes (freq: 0.00006), Latino in 2 of 25934 chromosomes (freq: 0.00008), European in 8 of 78198 chromosomes (freq: 0.0001), East Asian in 1 of 12748 chromosomes (freq: 0.00008), Finnish in 1 of 18938 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Ashkenazi Jewish, and South Asian populations. The p.Ser419= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003952801	SCV004770406	likely benign	STK11-related disorder	2019-03-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).