ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.892G>A (p.Glu298Lys) (rs201744589)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000206802 SCV001142530 likely benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.892G>A; p.Glu298Lys meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.
Ambry Genetics RCV000130033 SCV000184859 likely benign Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000206802 SCV000260657 uncertain significance Li-Fraumeni syndrome 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 298 of the TP53 protein (p.Glu298Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201744589, ExAC 0.009%). This variant has been observed in individual(s) affected with leukemia (PMID: 21747090). However, it is unclear if this variant emerged at relapse diagnosis or not. ClinVar contains an entry for this variant (Variation ID: 141483). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 30224644). 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.
Counsyl RCV000411322 SCV000488500 uncertain significance Li-Fraumeni syndrome 1 2016-04-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986055 SCV001134879 uncertain significance not provided 2019-03-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130033 SCV001342499 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355227 SCV001550050 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.Glu298Lys variant has been identified in 2 of 530 proband chromosomes (frequency: 0.004) of individuals affected with leukemia (Hof 2011). The variant was also identified in the following databases: dbSNP (ID: rs201744589) as “With Uncertain significance allele”, ClinVar (reported 3x as likely benign and uncertain significance by Ambry Genetics, Invitae and Counsyl), Cosmic (2x recurrence, endometrium, haematopoietic, Sinonasal and nasal cavity tissues, as carcinoma and lymphoid neoplasm) and IARC TP53 Database (7x somatic, 1x germline). The variant was not identified in Clinvitae, LOVD 3.0, UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was identified in control databases in 3 of 246268 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 2 of 33582 chromosomes (freq: 0.00006), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). It was not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu298Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355706 SCV001550662 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The TP53 p.Glu298Lys variant has been identified in 2 of 530 proband chromosomes (frequency: 0.004) of individuals affected with leukemia (Hof 2011). The variant was also identified in the following databases: dbSNP (ID: rs201744589) as “With Uncertain significance allele”, ClinVar (reported 3x as likely benign and uncertain significance by Ambry Genetics, Invitae and Counsyl), Cosmic (2x recurrence, endometrium, haematopoietic, Sinonasal and nasal cavity tissues, as carcinoma and lymphoid neoplasm) and IARC TP53 Database (7x somatic, 1x germline). The variant was not identified in Clinvitae, LOVD 3.0, UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was identified in control databases in 3 of 246268 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 2 of 33582 chromosomes (freq: 0.00006), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). It was not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu298Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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