ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.145G>C (p.Asp49His) (rs587780728)

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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 RCV000410497 SCV001737934 likely benign Li-Fraumeni syndrome 1 2021-05-06 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.125G>C (p.D49H) 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, BS2_Supporting.
Invitae RCV000123095 SCV000166395 uncertain significance Li-Fraumeni syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 49 of the TP53 protein (p.Asp49His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs587780728, ExAC 0.01%). This variant has been observed in individual(s) with sarcoma, lymphoma, pancreatic cancer, breast cancer, and in control individuals (PMID: 28902083, 27545002, 29667044, 30287823). ClinVar contains an entry for this variant (Variation ID: 135948). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 protein function (PMID: 12826609, 30224644, 12901974, 9207066, 15489903, 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.
Ambry Genetics RCV000129275 SCV000184035 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing The p.D49H variant (also known as c.145G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 145. The aspartic acid at codon 49 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in six patients from a cohort of 1685 Japanese adult patients with various cancers (Yamaguchi K et al. Biomed. Res., 2016;37:259-64). Of these cases, only one of the six met clinical criteria for Li-Fraumeni-Like syndrome (LFL), but this individual was also noted to carry the TP53 p.A159D germline alteration. Further, this alteration has been identified in a 15 year old boy with lymphocyte-predominant Hodgkin lymphoma, and was also identified in his sister who has a history of rhabdomyosarcoma at the age of 1.5 years (Yamazaki F et al. J. Pediatr. Hematol. Oncol. 2017 Sep). This alteration was shown to have a loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9), and increase VEGF expression in mammalian cells (Narendran A et al. Exp. Hematol. 2003 Aug;31:693-701). This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000410497 SCV000488754 uncertain significance Li-Fraumeni syndrome 1 2016-06-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129275 SCV000686722 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-20 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030740 SCV001193756 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000410497 SCV001282023 uncertain significance Li-Fraumeni syndrome 1 2017-04-27 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192616 SCV001360862 uncertain significance not specified 2019-03-14 criteria provided, single submitter clinical testing Variant summary: TP53 c.145G>C (p.Asp49His) results in a non-conservative amino acid change located in the transactivation domain 2 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246194 control chromosomes (gnomad). This variant has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and other cancers (Yamaguchi_2016, Yamazaki_2018, Ohmoto_2018). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Narendran_2003). The transfection experiment demonstrated the ability of p.Asp49His to increase the expression of VEGF. However, the association between this effect to Li-Fraumeni Syndrome is not clear. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.

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