Submissions for variant NM_000455.5(STK11):c.666C>T (p.Pro222=)

gnomAD frequency: 0.00005  dbSNP: rs542189325

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162395	SCV000212718	likely benign	Hereditary cancer-predisposing syndrome	2014-12-09	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	RCV000228328	SCV000284873	benign	Peutz-Jeghers syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000228328	SCV000410741	likely benign	Peutz-Jeghers syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000228328	SCV000488076	likely benign	Peutz-Jeghers syndrome	2015-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001704153	SCV000514796	likely benign	not provided	2021-03-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162395	SCV000686673	benign	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423666	SCV000920280	benign	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.666C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00054 in 268862 control chromosomes, predominantly at a frequency of 0.0043 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 688 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. To our knowledge, no occurrence of c.666C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000423666	SCV001469920	benign	not specified	2019-10-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000228328	SCV002057423	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162395	SCV002531722	benign	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149986	SCV003838166	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000228328	SCV004015566	benign	Peutz-Jeghers syndrome	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228328	SCV004017961	benign	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV001704153	SCV004139039	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	STK11: BP4, BP7, BS1
All of Us Research Program, National Institutes of Health	RCV000228328	SCV004818883	benign	Peutz-Jeghers syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356479	SCV001551660	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Pro222= variant was not identified in the literature nor was it identified in Cosmic, MutDB, Zhejiang University Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs542189325 as “With Likely benign, other allele”), ClinVar (classified benign by Invitae and Color Genomics Inc and as likely benign by Ambry Genetics, Illumina, Counsyl and GeneDx), and LOVD 3.0 (1x). The variant was identified in control databases in 145 of 268862 chromosomes (1 homozygous) at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 132 of 30482 chromosomes (freq: 0.004, 1 homozygous), African in 1 of 22816 chromosomes (freq: 0.00004), Latino in 3 of 34078 chromosomes (freq: 0.00009), European Non-Finnish in 6 of 121580 chromosomes (freq: 0.00005), and East Asian in 3 of 18654 chromosomes (freq: 0.0002), while it not observed in the Other, Ashkenazi Jewish or Finnish populations. The p.Pro222= 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. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.