Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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. |
Gene |
RCV000590586 | SCV000149642 | likely benign | not provided | 2020-06-12 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14559903, 10362336, 26483394, 20128691, 17606709, 7706467, 21343334, 25637381, 26086041, 17318340, 19367569, 24728327, 9067756, 9285560, 10432928, 21232794, 27194209, 25980754, 28861920, 29058119, 15580553, 29979965, 30352134, 29467486, 30262806, 31016814, 30840781, 31289210, 33300245) |
Ambry Genetics | RCV000115733 | SCV000185528 | likely benign | Hereditary cancer-predisposing syndrome | 2019-03-18 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Invitae | RCV000991139 | SCV000219130 | likely benign | Li-Fraumeni syndrome | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000590586 | SCV000232075 | uncertain significance | not provided | 2014-08-22 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000122177 | SCV000597513 | uncertain significance | not specified | 2016-09-13 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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 Diagnostics, |
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 | |
Institute for Clinical Genetics, |
RCV000590586 | SCV002011127 | likely benign | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV001798339 | SCV002042835 | likely benign | Breast and/or ovarian cancer | 2023-03-23 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000590586 | SCV002048467 | benign | not provided | 2021-05-08 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000115733 | SCV002532706 | benign | Hereditary cancer-predisposing syndrome | 2021-03-26 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV000122177 | SCV002550969 | benign | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000663295 | SCV004017835 | uncertain significance | Li-Fraumeni syndrome 1 | 2023-04-11 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Prevention |
RCV003952552 | SCV004775259 | likely benign | TP53-related condition | 2021-02-17 | criteria provided, single submitter | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
ITMI | RCV000122177 | SCV000086392 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
CSER _CC_NCGL, |
RCV000148915 | SCV000190661 | uncertain significance | Rhabdomyosarcoma | 2014-06-01 | no assertion criteria provided | research | |
Genome Diagnostics Laboratory, |
RCV000122177 | SCV001808675 | benign | not specified | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000590586 | SCV001958124 | likely benign | not provided | no assertion criteria provided | clinical testing |