Submissions for variant NM_000546.6(TP53):c.642T>G (p.His214Gln)

gnomAD frequency: 0.00004  dbSNP: rs587781386

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129218	SCV000183969	likely benign	Hereditary cancer-predisposing syndrome	2018-07-27	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	RCV001283869	SCV000211753	likely benign	not provided	2018-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14559903, 23259501, 16728565, 15781620, 29979965, 31321604)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195927	SCV000253315	likely benign	Li-Fraumeni syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000410083	SCV000488187	uncertain significance	Li-Fraumeni syndrome 1	2016-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129218	SCV000911487	likely benign	Hereditary cancer-predisposing syndrome	2017-12-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283869	SCV001469325	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	The TP53 c.642T>G (p.His214Gln) variant has been reported in the published literature in individuals affected with breast cancer (PMIDs: 35980532 (2022), 35264596 (2022), 23259501 (2012)) and lung cancer (PMID: 31321604 (2019)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMIDs: 15781620 (2005), 12826609 (2003)). The frequency of this variant in the general population, 0.00014 (5/34590 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000129218	SCV002530478	likely benign	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267869	SCV002551025	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410083	SCV004017885	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267869	SCV005076607	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.642T>G (p.His214Gln) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251466 control chromosomes, predominantly at a frequency of 0.00014 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.642T>G has been reported in the literature as a germline change in individuals affected with Lung cancer and breast cancer (Rucker_2012, Pereira_2022, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Somatic change of this variant has also been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 31321604, 27895058, 16818505, 11782540, 22915647, 35264596, 26230955, 21519010, 20407015, 27463065, 30327374, 17606709, 21343334, 26585234, NCCN_AML, NCCN_MDS, NCCN_MPN, 25952993, 27276561, 35980532, 22186996, 27680515, 27959731). ClinVar contains an entry for this variant (Variation ID: 140943). Based on the evidence outlined above, the variant was classified as uncertain significance.