Submissions for variant NM_000455.5(STK11):c.1229C>T (p.Ala410Val)

gnomAD frequency: 0.00002  dbSNP: rs372329880

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213038	SCV000149506	likely benign	not provided	2020-04-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30093976)
Ambry Genetics	RCV000115597	SCV000185482	likely benign	Hereditary cancer-predisposing syndrome	2019-09-28	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	RCV000200053	SCV000254545	likely benign	Peutz-Jeghers syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115597	SCV000691481	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 410 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 30093976, 31871109). This variant has been identified in 5/191680 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	RCV000200053	SCV002057337	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281935	SCV002572402	uncertain significance	not specified	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1229C>T (p.Ala410Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 191680 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1229C>T has been reported in the literature in individuals reported with breast cancer who have undergone multi gene panel testing (examples: Chan_2018 and Adedokun_2020). These reports classified the variant as VUS and 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign(n=2) and VUS(n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV000200053	SCV002580367	uncertain significance	Peutz-Jeghers syndrome	2021-11-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200053	SCV004819016	uncertain significance	Peutz-Jeghers syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 410 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 30093976, 31871109). This variant has been identified in 5/191680 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002281935	SCV005089920	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing