ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1193C>T (p.Ala398Val) (rs768058962)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163934 SCV000214530 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
Invitae RCV000234273 SCV000284849 uncertain significance Peutz-Jeghers syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 398 of the STK11 protein (p.Ala398Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with suspected Lynch syndrome and in an individual with breast cancer (PMID: 25980754, 26898890). ClinVar contains an entry for this variant (Variation ID: 184646). 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 valine 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.
GeneDx RCV000657114 SCV000569242 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1193C>T at the cDNA level, p.Ala398Val (A398V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been observed in one individual with breast cancer and a family history of ovarian cancer, as well as in at least one individual with a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015, Caminsky 2016). STK11 Ala398Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Ala398Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486365 SCV000602210 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing
Counsyl RCV000234273 SCV000784824 uncertain significance Peutz-Jeghers syndrome 2017-01-04 criteria provided, single submitter clinical testing
Color RCV000163934 SCV000902842 likely benign Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing

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