ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.580G>A (p.Asp194Asn) (rs121913315)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168375 SCV000219066 pathogenic Peutz-Jeghers syndrome 2020-04-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 194 of the STK11 protein (p.Asp194Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals and families affected with Peutz-Jeghers syndrome (PJS) (PMID: 10408777, 23718779, 16582077, 12865922, 25226294, 17026623, 20435009, 16287113) and colorectal polyposis (PMID: 23399955). This variant was also reported to segregate with PJS in a family (PMID: 10408777). ClinVar contains an entry for this variant (Variation ID: 188348). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This sequence change falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein (PMID: 19892943, 14976552, 14517248, 21189378, 23240097). This indicates that this region of the protein may be critical for proper protein function. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000708629 SCV000331163 pathogenic not provided 2015-09-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492479 SCV000580886 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-12 criteria provided, single submitter clinical testing The p.D194N variant (also known as c.580G>A), located in coding exon 4 of the STK11 gene, results from a G to A substitution at nucleotide position 580. The aspartic acid at codon 194 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been described in multiple families meeting clinical diagnostic criteria for Peutz-Jeghers syndrome (PJS) (Westerman AM et al. Hum. Mutat. 1999;13:476-81; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Chow E et al. Clin. Genet. 2006 Nov;70:409-14; Borun P et al. BMC Med. Genet. 2013 May;14:58; Hearle NC et al. J. Med. Genet. 2006 Apr;43:e15; Lim W et al. Br. J. Cancer. 2003 Jul;89:308-13; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). This alteration has also been reported in two unrelated individuals with juvenile, adenomatous, and hyperplastic polyps (Ngeow J et al. Gastroenterology. 2013 Jun;144:1402-9, 1409.e1-5). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneKor MSA RCV000708629 SCV000821781 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a substitution of aspartic acid with asparagine at position 194 of the STK11 protein. This particular aspartic acid is highly conserved and there is small physicochemical variation caused by the change. The mutation is absent from population databases but it is reported in literature in individual or families affected by colorectal cancer and the Peutz-Jeghers syndrome (PMID:23399955, PMID: 10408777, PMID: 16582077). The mutation is located in a region of the protein that is considered to be particularly important for its proper function thus the mutation frequency in this region is high, thus it is considered a mutational 'hotspot' region (PMID: 14976552, PMID:14517248, PMID:21189378, PMID:23240097). The mutation database ClinVar contains entries for this variant (Variation ID: 188348).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000708629 SCV001134844 pathogenic not provided 2019-04-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/252614 chr). Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. One de novo case with parental identity confirmed.
Color Health, Inc RCV000492479 SCV001340646 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing
GeneDx RCV000708629 SCV001804348 pathogenic not provided 2019-07-26 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32462036, 31159747, 28152038, 16287113, 20393878, 26233267, 25226294, 10408777, 23718779, 15863673, 17026623, 26056085, 27081308, 12865922, 23430953, 20435009, 16582077, 17924967, 23399955, 30528796)
Database of Curated Mutations (DoCM) RCV000445048 SCV000505689 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427095 SCV000505690 likely pathogenic Lung adenocarcinoma 2016-05-13 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000708629 SCV001548592 pathogenic not provided no assertion criteria provided clinical testing The STK11 p.Asp194Asn variant was identified in 18 of 1868 proband chromosomes (frequency: 0.01) from individuals or families with Peutz-Jeghers Syndrome and is consistently reported as pathogenic in the literature (Aretz 2005, Borun 2013, Chow 2006, Crocker 2014, De Rosa 2010, Hearle 2006, Lim 2003, Ngeow 2013, Schumacher 2005, Westerman 1999, de Leng 2007, Yang 2010). The variant was also identified in dbSNP (ID: rs121913315) as “With Pathogenic allele”, in ClinVar (as pathogenic by Invitae and EGL Diagnostics and as likely pathogenic by Ambry Genetics), Clinvitae (5x), Cosmic (seen in prostate, breast, small intestine, and lung cancer), LOVD 3.0 (as pathogenic), and Zhejiang University Database (8x as pathogenic). The variant was not identified in MutDB or Insight Hereditary Tumors Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Asp194 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Asparagine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000708629 SCV001744792 pathogenic not provided no assertion criteria provided clinical testing

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