Submissions for variant NM_000546.6(TP53):c.986C>T (p.Thr329Ile)

dbSNP: rs969930693

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808332	SCV000948438	uncertain significance	Li-Fraumeni syndrome	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 329 of the TP53 protein (p.Thr329Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 34423517). ClinVar contains an entry for this variant (Variation ID: 652718). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 20978130, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001183900	SCV001349748	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 329 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have demonstrated no affect of this variant on tetramer formation, tetramer stability, or TP53 transactivation activity (PMID: 12826609, 20978130, 30224644). This variant has been reported in an individual affected with breast cancer (PMID: 34423517). This variant has been identified in 1/251390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824889	SCV002074302	uncertain significance	not specified	2022-01-16	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.986C>T (p.Thr329Ile) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) 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 4e-06 in 251390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knolwedge, c.986C>T has not been reported in the literature in individuals affected with Li-Fraumeni Syndrome. However, it has been reported in a variety of somatic cancers such as an instance of BRCA1-related breast tumors in the presence of other deleterious common hotspot p53 variants (example, Holstege_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example Kato_2003). These demonstrated a functional outcome based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV002290454	SCV002582877	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001183900	SCV002583229	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001183900	SCV002691237	likely benign	Hereditary cancer-predisposing syndrome	2022-10-12	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002290454	SCV004015239	uncertain significance	Li-Fraumeni syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 329 of the TP53 protein. results in a non-conservative amino acid change located in the p53. Computational prediction depending on ( M-CAP, SIFT, FATHMM-MKL, MutPred, BayesDel ,MetaLR and REVEL) suggests that this variant may have deleterious impact on protein structure and function . This variant has been identified in 1/251390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has not been reported in individuals affected with hereditary cancer in the literature. Experimental functional studies have demonstrated no affect of this variant on tetramer formation, tetramer stability, or TP53 transactivation activity (PMID: 12826609, 20978130, 30224644). However, it has been reported in a variety of somatic cancers such as an instance of BRCA1-related breast tumors in the presence of other deleterious common hotspot p53 variants (Holstege_2009 and others). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (ID:652718) without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000808332	SCV004823739	uncertain significance	Li-Fraumeni syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 329 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated no affect of this variant on tetramer formation, tetramer stability, or TP53 transactivation activity (PMID: 12826609, 20978130, 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.