Submissions for variant NM_000546.5(TP53):c.319T>C (p.Tyr107His)

gnomAD frequency: 0.00028  dbSNP: rs368771578

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991146	SCV001142553	benign	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.319T>C variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 107 (p.Tyr107His). 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: ClinVar SCV: SCV000172807.10). The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0202 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). 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: BS1, BS2, BS3_supporting, BP4 (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024).
Ambry Genetics	RCV000128936	SCV000172807	likely benign	Hereditary cancer-predisposing syndrome	2019-02-16	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.
GeneDx	RCV000588191	SCV000211739	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15073856, 24729566, 21373875, 26580448, 26206375, 27626311, 24797764, 28056804, 25896519, 28861920, 29979965, 30352134, 33300245)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991146	SCV000285186	likely benign	Li-Fraumeni syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000411273	SCV000489333	uncertain significance	Li-Fraumeni syndrome 1	2016-09-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235219	SCV000597523	likely benign	not specified	2018-04-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588191	SCV000602266	likely benign	not provided	2022-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235219	SCV000697439	benign	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.319T>C (p.Tyr107His) results in a conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Functional studies based on the overall transcriptional activity in yeast assays classified this variant as partially functional (Kato_2003). The variant allele was found at a frequency of 0.00012 in 282734 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 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 African or African-American origin. In addition, this variant was observed in old females, older than age 70 years who have never had cancer (FLOSSIES database). This variant has been reported in cancer patients without strong evidence for causality. Eight ClinVar submitters, including one expert panel (ClinGen TP53 Variant Curation Expert Panel, benign), (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (6x) and benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000128936	SCV000910800	likely benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000991146	SCV001439183	benign	Li-Fraumeni syndrome	2020-09-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128936	SCV002530446	benign	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498638	SCV002810023	likely benign	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-04-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411273	SCV004017832	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492581	SCV004239784	benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917413	SCV004734797	likely benign	TP53-related disorder	2020-03-27	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).