ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.704A>G (p.Asn235Ser) (rs144340710)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000991139 SCV001142532 benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a minor allele frequency of 0.0003175 (0.03%, 41/129,118 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BS1). The 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). This variant also segregates to the opposite side of a family who meets Li-Fraumeni syndrome criteria. (BS4; PMID: 17318340). The proband in this same family has a pathogenic variant (TP53 c.560-1G>A) in trans with this variant. (BP2; PMID: 17318340). Finally, this variant has been observed in at least 4 60+ year old females without a cancer diagnosis (BS2_Supporting; FLOSSIES database - https://whi.color.com).In summary, TP53 c.704A>G; p.Asn235Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BP4, BS3, BS4, BP2, BS2_Supporting.
GeneDx RCV000122177 SCV000149642 likely benign not specified 2017-10-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115733 SCV000185528 likely benign Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000991139 SCV000219130 likely benign Li-Fraumeni syndrome 2020-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590586 SCV000232075 uncertain significance not provided 2014-08-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000122177 SCV000597513 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122177 SCV000697446 benign not specified 2021-03-22 criteria provided, single submitter clinical testing Variant summary: TP53 c.704A>G (p.Asn235Ser) results in a conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251784 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Though the variant, c.704A>G, has been reported in the literature in individuals affected with various tumor types, it was also found in several healthy controls (de Andrade 2017, FLOSSIES database). Moreover, the variant was shown not to co-segregate with disease in at least one LFS family, who also carried a pathogenic splice site TP53 variant (van Hest 2007), suggesting that the variant of interest was not the cause of LFS in this family. Functional studies have shown this variant to have normal DNA binding properties and a well preserved transcriptional activity (>70% of normal activity), while the majority of known pathogenic TP53 variants have a transcriptional activity of <20% (Gonzalez 2011, Monti 2011, van Hest 2007, Soussi 2005). Additionally, immunohistochemical staining of tumors from carriers of the variant showed no expression of p53, while positive staining is commonly seen for pathogenic TP53 missense mutations (van Hest 2007). Nine other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen TP53 Variant Curation Expert Panel) cite the variant as likely benign/benign (n=8) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000663295 SCV000786543 likely benign Li-Fraumeni syndrome 1 2018-05-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115733 SCV000902685 likely benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
Mendelics RCV000989714 SCV001140256 benign Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590586 SCV001469326 likely benign not provided 2019-11-27 criteria provided, single submitter clinical testing
ITMI RCV000122177 SCV000086392 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148915 SCV000190661 uncertain significance Rhabdomyosarcoma (disease) 2014-06-01 no assertion criteria provided research

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