Submissions for variant NM_000455.5(STK11):c.1027G>A (p.Asp343Asn)

gnomAD frequency: 0.00006  dbSNP: rs368547224

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129286	SCV000184047	likely benign	Hereditary cancer-predisposing syndrome	2021-05-20	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.
GeneDx	RCV000656982	SCV000211723	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or medulloblastoma and also in unaffected controls (Zhang et al., 2015; Momozawa et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 27043212, 26354930, 25742471, 26580448, 28492532, 30287823, 29106415, 29325035, 34746883, 33471991, 28900777, 30883245)
Invitae	RCV000197027	SCV000254535	uncertain significance	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 343 of the STK11 protein (p.Asp343Asn). This variant is present in population databases (rs368547224, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 140986). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129286	SCV000537536	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 343 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with an unspecified cancer (PMID: 25742471), pediatric medulloblastoma (PMID: 26580448), prostate cancer (PMID: 31214711), and breast cancer (PMID: 31214711, 33471991), but also in unaffected controls (PMID: 33471991). This variant has also been reported in four individuals age 70 years or older without cancer (FLOSSIES database; https://whi.color.com/variant/19-1223090-G-A). This variant has been identified in 5/242452 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656982	SCV000602203	likely benign	not provided	2023-08-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656982	SCV000806067	uncertain significance	not provided	2017-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213030	SCV000918291	uncertain significance	not specified	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1027G>A (p.Asp343Asn) 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 1.8e-05 in 340026 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1027G>A has been reported in the literature in individuals affected with breast cancer (Momozawa_2018, Weitzel_2019) as well as in controls (Okawa_2023). These reports 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. Ten ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=9) and likely benign (n=1). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 26354930, 30287823, 31206626, 25742471, 26580448, 36243179). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000197027	SCV002057902	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129286	SCV002531620	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000197027	SCV002579035	uncertain significance	Peutz-Jeghers syndrome	2022-06-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656982	SCV004139041	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	STK11: PM2:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000656982	SCV004224518	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	BP4
All of Us Research Program, National Institutes of Health	RCV000197027	SCV004818959	uncertain significance	Peutz-Jeghers syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 343 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with an unspecified cancer (PMID: 25742471), pediatric medulloblastoma (PMID: 26580448), prostate cancer (PMID: 31214711), and breast cancer (PMID: 31214711, 33471991), but also in unaffected controls (PMID: 33471991). This variant has also been reported in four individuals age 70 years or older without cancer (FLOSSIES database; https://whi.color.com/variant/19-1223090-G-A). This variant has been identified in 5/242452 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.
True Health Diagnostics	RCV000129286	SCV000788215	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing