Submissions for variant NM_000546.6(TP53):c.1060C>A (p.Gln354Lys)

gnomAD frequency: 0.00002  dbSNP: rs755394212

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000469791	SCV001949924	benign	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	The NM_000546.6: c.1060C>A variant in TP53 is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 354 (p.Gln354Lys). This variant has been observed in 4-7 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_Moderate; internal lab contributors). This variant has an allele frequency of 0.00001441 (17/1179974 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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). Computational predictor scores (BayesDel = -0.28; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 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_moderate, BS3, BP4_Moderate, PM2_supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024).
Ambry Genetics	RCV000222255	SCV000275352	likely benign	Hereditary cancer-predisposing syndrome	2021-02-02	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	RCV000469791	SCV000545335	uncertain significance	Li-Fraumeni syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 354 of the TP53 protein (p.Gln354Lys). This variant is present in population databases (rs755394212, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24549055, 34326862). ClinVar contains an entry for this variant (Variation ID: 231485). Advanced modeling performed at Invitae incorporating data from internal and/or published 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). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626710	SCV000747413	uncertain significance	Colorectal polyposis; Colonic neoplasm	2017-01-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000663226	SCV000786422	uncertain significance	Li-Fraumeni syndrome 1	2018-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222255	SCV001359324	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 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	RCV001269248	SCV001448570	uncertain significance	not specified	2020-11-27	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.1060C>A (p.Gln354Lys) results in a conservative amino acid change located in the p53, tetramerization domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250864 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1060C>A has been reported in the literature in at-least one individual affected with breast cancer (example, Castero_2014). This report(s) does 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 (Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Five 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.
Sema4, Sema4	RCV000222255	SCV002530422	likely benign	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663226	SCV004017866	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.
All of Us Research Program, National Institutes of Health	RCV000469791	SCV004823723	uncertain significance	Li-Fraumeni syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 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.