Submissions for variant NM_000455.5(STK11):c.920+5G>A

gnomAD frequency: 0.00008  dbSNP: rs587780013

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588193	SCV000149514	uncertain significance	not provided	2021-06-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in at least one individual with an unspecified cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 31422818, 27535533, 28873162)
Ambry Genetics	RCV000115605	SCV000186855	likely benign	Hereditary cancer-predisposing syndrome	2019-10-08	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.
Invitae	RCV000204699	SCV000261739	likely benign	Peutz-Jeghers syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588193	SCV000602241	uncertain significance	not provided	2019-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213026	SCV000696732	uncertain significance	not specified	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.920+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 1.9e-05 in 205340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 920+5G>A has been reported in the literature in one individual without clinical information (Gordon_2019) and in another individual undergoing surveillance for prostate cancer (Brady_2022). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: eight classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213026	SCV000712641	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	The c.920+5G>A variant in STK11 has not been previously reported in individuals with Peutz-Jeghers syndrome, but has been identified in 1/2138 of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587780013). This variant is located in the 5' splice region. Although n ucleotide substitutions at +5 position of the intron are relatively common cause s of aberrant splicing, computational tools do not suggest an impact to splicing . However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.920+5G>A variant is uncertain.
Counsyl	RCV000204699	SCV000784862	uncertain significance	Peutz-Jeghers syndrome	2017-01-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000204699	SCV000839422	uncertain significance	Peutz-Jeghers syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115605	SCV000910053	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 7 of the STK11 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. This variant has been reported in an individual affected with prostate cancer (PMID: 35467778). This variant has been identified in 4/205340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000204699	SCV002057299	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204699	SCV004018012	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.