Submissions for variant NM_000546.6(TP53):c.704A>G (p.Asn235Ser)

gnomAD frequency: 0.00025  dbSNP: rs144340710

Total submissions: 24

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	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.704A>G variant in TP53 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 235 (p.Asn235Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor: SCV000185528.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340). Computational predictor scores (BayesDel = -0.0342; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BS4, BP4_Moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024)
GeneDx	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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991139	SCV000219130	likely benign	Li-Fraumeni syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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 Diagnostics, LLC DBA Color Health	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, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590586	SCV002011127	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798339	SCV002042835	likely benign	Breast and/or ovarian cancer	2023-03-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590586	SCV002048467	benign	not provided	2024-04-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115733	SCV002532706	benign	Hereditary cancer-predisposing syndrome	2021-03-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122177	SCV002550969	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122177	SCV004848869	likely benign	not specified	2019-03-22	criteria provided, single submitter	clinical testing	The p.Asn235Ser variant in TP53 is classified as Likely Benign because it has been identified in 0.03% (41/129118) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, although it has been reported in individuals with cancer (Diller 1995, Ponten 1997, Auer 1999, Huusko,1999), this variant was shown not to segregate with disease in at least 4 affected individuals from 1 family (van Hest 2007). In this family, the variant was identified in individuals with disease, who carried an additional pathogenic variant sufficient to explain their clinical presentation. The p.Asn235Ser variant has been reported in ClinVar (Variation ID: 127821). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein and in vitro functional studies provide additional evidence that this variant does not impact protein function (van Hest 2007). ACM/AMP Criteria applied: BS1_Supporting, BP4, BS4, BS3_Supporting
CeGaT Center for Human Genetics Tuebingen	RCV000590586	SCV005435201	benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	TP53: BS3:Supporting, BS1, BS2
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	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122177	SCV001808675	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590586	SCV001958124	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952552	SCV004775259	likely benign	TP53-related disorder	2021-02-17	no assertion criteria provided	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).