ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.464+9G>A (rs376313955)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213011 SCV000171885 benign not specified 2014-03-26 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 RCV000131962 SCV000187019 likely benign Hereditary cancer-predisposing syndrome 2013-08-08 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 RCV000198311 SCV000252701 benign Peutz-Jeghers syndrome 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000198311 SCV000410738 benign Peutz-Jeghers syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131962 SCV000576425 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213011 SCV000602226 likely benign not specified 2016-12-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131962 SCV000686656 benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587711 SCV000696720 benign not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: The STK11 c.464+9G>A variant affects a non-conserved intronic nucleotide not widely known to affect splicing. Mutation Taster predicts a benign outcome for this variant, and 4/5 Alamut algorithms predict no significant change to splicing. This variant was found in 39/36972 control chromosomes at a frequency of 0.0010549, which is about 190 times the maximal expected frequency of a pathogenic STK11 allele (0.0000056), suggesting this variant is benign. In addition, several clinical laboratories classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Additionally, the variant co-occurred with a pathogenic PMS2 variant (c.2186_2187delTC) in one internal specimen. Taken together, this variant was classified as benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000213011 SCV000859972 likely benign not specified 2018-03-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587711 SCV000889860 benign not provided 2017-12-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000213011 SCV000692045 benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356286 SCV001551411 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The STK11 c.464+9G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs376313955) as "With other allele", in ClinVar (5x Benign by Invitae, GeneDx and three other submitters, 5x likely benign by Ambry Genetics and four other submitters), and in LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 165 of 203546 chromosomes at a frequency of 0.0008, 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: African in 132 of 18030 chromosomes (freq: 0.007), Other in 4 of 5186 chromosomes (freq: 0.0008), Latino in 26 of 27178 chromosomes (freq: 0.001), European in 2 of 87470 chromosomes (freq: 0.00002) and East Asian in 1 of 13646 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. 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. However, this information is not predictive enough to assume 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.

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