Submissions for variant NM_000455.5(STK11):c.96C>G (p.Thr32=)

dbSNP: rs79175212

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123069	SCV000166364	benign	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000213009	SCV000211691	benign	not specified	2014-09-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000160981	SCV000213653	likely benign	Hereditary cancer-predisposing syndrome	2015-03-15	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.
Counsyl	RCV000123069	SCV000487860	likely benign	Peutz-Jeghers syndrome	2015-11-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160981	SCV000686710	benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213009	SCV000888652	benign	not specified	2021-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213009	SCV000918279	benign	not specified	2018-03-28	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.96C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.00028 in 275788 control chromosomes (gnomAD). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 624-folds higher than 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 a benign polymorphism found primarily in population(s) of East Asian origin. The variant, c.96C>G, has been reported in the literature in individuals affected with mucinous MDA, breast cancer, and small-intestinal cancer (Kuragaki_2003, Lee_2017, Nakagawa_1999). Nakagawa_1999 indicates that the variant was only present in the tumor sample and not germline. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000123069	SCV001287377	benign	Peutz-Jeghers syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome-Nilou Lab	RCV000123069	SCV002057394	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160981	SCV002526966	benign	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000123069	SCV004017997	benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV003407530	SCV004139038	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	STK11: BP4, BP7, BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357485	SCV001552969	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Thr32= variant was identified in the literature as a somatic variant in adenocarcinoma of the small intestine or uterine cervix in 2 Japanese patients (Nakagawa_1999_10429655, Kuragaki_2003_12533684). The variant was also identified in dbSNP (ID: rs79175212) as “With other allele”, ClinVar and Clinvitae (3x classified as benign by Invitae, GeneDx, Quest Diagnostics; 2x classified as likely benign by Ambry Genetics, Counsyl), COSMIC (2x confirmed somatic in the cases cited above), and the Zhejiang Colon Cancer Database (1x classified as probably no pathogenicity). The variant was not identified in MutDB, LOVD 3.0, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 78 of 275788 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23862 chromosomes (freq: 0.00004), “Other” in 1 of 6412 chromosomes (freq: 0.0002), Latino in 1 of 34378 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 125910 chromosomes (freq: 0.000008), East Asian in 74 of 18852 chromosomes (freq: 0.004); it was not observed in the Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr32= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.