Submissions for variant NM_000455.5(STK11):c.992G>A (p.Arg331Gln)

gnomAD frequency: 0.00006  dbSNP: rs371264852

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130707	SCV000185594	likely benign	Hereditary cancer-predisposing syndrome	2023-03-02	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	RCV000199024	SCV000254562	likely benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000199024	SCV000488391	uncertain significance	Peutz-Jeghers syndrome	2016-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000486850	SCV000565598	likely benign	not provided	2021-03-19	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: 30287823, 28135145, 29106415)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000199024	SCV000891065	uncertain significance	Peutz-Jeghers syndrome	2022-12-28	criteria provided, single submitter	clinical testing	The STK11 c.992G>A (p.Arg331Gln) missense change has a maximum subpopulation frequency of 0.0075% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 30287823). In addition, four individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130707	SCV000902884	likely benign	Hereditary cancer-predisposing syndrome	2016-02-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000199024	SCV001140946	uncertain significance	Peutz-Jeghers syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486850	SCV001470113	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000199024	SCV002057301	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465530	SCV002761027	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465530	SCV003800770	likely benign	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.992G>A (p.Arg331Gln) results in a 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 4.8e-05 in 231544 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.992G>A has been reported in the literature in individuals affected with colorectal cancer (Yurgelun_2017) and breast and/or ovarian cancer (Krivokuca_2022, and Momozawa_2018); however, authors classified the variant as VUS. These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1852_1854del, p.K618del), providing supporting evidence for a benign role (Yurgelun_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV000199024	SCV004018016	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.