ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1093C>T (p.His365Tyr)

dbSNP: rs267605075
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000701624 SCV001142538 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.1093C>T; p.His365Tyr 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 RCV000129635 SCV000184430 likely benign Hereditary cancer-predisposing syndrome 2020-08-19 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000701624 SCV000830434 uncertain significance Li-Fraumeni syndrome 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 365 of the TP53 protein (p.His365Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs267605075, ExAC 0.002%). This variant has been observed in an individual with childhood soft tissue sarcoma (PMID: 12610779). ClinVar contains an entry for this variant (Variation ID: 80708). This variant has been reported not to substantially affect TP53 protein function (PMID: 21343334, 12826609). 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.
Illumina Laboratory Services,Illumina RCV001127281 SCV001286576 uncertain significance Li-Fraumeni syndrome 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Health, Inc RCV000129635 SCV001359322 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-17 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 365 of the TP53 protein. Computational prediction tools and conservation analyses indicate that this change may affect protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Functional assays have been inconsistent and have not demonstrated a significant functional deficit (PMID 12826609, 21343334, 24256616). The variant has been identified in two individuals affected with cancer (PMID 12610779, 17606709). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 RCV000129635 SCV000788224 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358057 SCV001553701 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.His365Tyr variant was identified in 2 of 246 proband chromosomes (frequency: 0.008) from individuals or families with lung cancer or soft tissue sarcoma (Hayes 1999, Hwang 2003). The variant was also identified in dbSNP (ID: rs267605075) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics and True Health Diagnostics), Cosmic (1x in Stomach tissue), and in IARC TP53 Database (3x). The variant was not identified in COGR, or LOVD 3.0 databases. The variant was identified in control databases in 1 of 244474 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 110730 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His365 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In yeast-based systematic analysis the variant was classified as a partial deficiency allele based on its ability to transactivate a set of human target sequences and showed ~25% of wild-type activity toward at least one response element (Monti 2007, Monti 2011). 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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