ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.666C>T (p.Pro222=) (rs542189325)

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Total submissions: 9
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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: 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.
Invitae RCV000228328 SCV000284873 benign Peutz-Jeghers syndrome 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Health, Inc 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
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.

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