Submissions for variant NM_000455.5(STK11):c.1041G>A (p.Ala347=)

dbSNP: rs537906142

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163988	SCV000214588	likely benign	Hereditary cancer-predisposing syndrome	2014-12-23	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	RCV000220705	SCV000279184	uncertain significance	not specified	2015-10-12	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.1041G>A at the DNA level. Although the variant is silent at the coding level, preserving an Alanine at codon 347, this variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004); however, splicing models at our laboratory do not predict an effect on splicing. STK11 c.1041G>A was not observed at a significant allele frequency in 1000 Genomes. The nucleotide which is altered, a guanine (G) at base 1041, is not conserved across species. Based on currently available information, it is unclear whether STK11 c.1041G>A is pathogenic or benign. We consider this to be a variant of uncertain significance.
Invitae	RCV000233264	SCV000284840	benign	Peutz-Jeghers syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587275	SCV000696700	benign	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.1041G>A (p.Ala347Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant changes in ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. Although the variant has been identified in at least one individual with hamartomatous polyps and was suggested to result in abnormal splicing (Wei 2003, Amos 2004), these studies provided no functional evidence to that effect and this report predated the development of large scale control population databases. The variant was found in the large control database ExAC in 17 of 95258 control chromosomes from all ethnicities, but was predominantly observed in the South Asian subpopulation at a frequency of 0.001139 (15/13164). This frequency is about 73 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000156), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. Multiple clinical diagnostic laboratories have classified this variant with conflicting interpretations, including uncertain significance (1x in ClinVar), likely benign (1x in ClinVar), and benign (1x in ClinVar). Taken together, this variant is classified as benign.
Counsyl	RCV000233264	SCV000785044	likely benign	Peutz-Jeghers syndrome	2017-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587275	SCV000888634	benign	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163988	SCV000902985	likely benign	Hereditary cancer-predisposing syndrome	2016-06-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163988	SCV002531623	benign	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000233264	SCV004017919	benign	Peutz-Jeghers syndrome	2023-04-12	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.
PreventionGenetics, part of Exact Sciences	RCV003937503	SCV004765754	likely benign	STK11-related disorder	2020-03-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358350	SCV001554055	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The STK11 p.Ala347Ala variant was identified in 1 of 84 proband chromosomes (frequency: 0.01) from individuals or families with Peutz-Jaghers Syndrome (Amos 2004). The variant was identified in dbSNP (rs537906142) as “with likely benign, uncertain significance allele”, in ClinVar (interpreted as "benign" by Invitae and 2 others, "likely benign" by Ambry Genetics and "uncertain significance" by GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 27 of 241,514 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant as this frequency is well above the known prevalence of Peutz-Jagher Syndrome (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 109,548 chromosomes (freq: 0.000009), Finnish in 1 of 21,340 chromosomes (freq: 0.00005), and South Asian in 25 of 30,278 chromosomes (freq: 0.0008). The variant was not observed in the African, Other, Latino, Ashkenazi Jewish, or East Asian populations. The p.Ala347= 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted the creation of a new splice site. 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.