ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1130C>T (p.Ala377Val) (rs199973552)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130754 SCV000185645 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000195574 SCV000254540 uncertain significance Peutz-Jeghers syndrome 2018-11-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 377 of the STK11 protein (p.Ala377Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs199973552, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colorectal cancer (PMID: 27696107). ClinVar contains an entry for this variant (Variation ID: 141991). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000483853 SCV000565600 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1130C>T at the cDNA level, p.Ala377Val (A377V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has been identified in an individual with colorectal and endometrial cancer, whose colorectal tumor showed microsatellite instability and loss of MSH6 protein by immunohistochemistry (Rohlin 2017). STK11 Ala377Val was observed at an allele frequency of 0.02% (9/54446) in individuals of European Non-Finnish ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. STK11 Ala377Val occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Ala377Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130754 SCV000686594 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000195574 SCV000785083 uncertain significance Peutz-Jeghers syndrome 2017-04-07 criteria provided, single submitter clinical testing

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