ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1142G>C (p.Gly381Ala) (rs765419233)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163414 SCV000213957 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000163414 SCV000910061 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587411 SCV000696703 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.1142G>C variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001% which does not exceed the maximal expected allele frequency for a pathogenic variant in STK11 (0.00139%). 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. One reputable clinical lab has classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000811562 SCV000951834 uncertain significance Peutz-Jeghers syndrome 2018-09-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 381 of the STK11 protein (p.Gly381Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs765419233, ExAC 0.002%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 184219). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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