Submissions for variant NM_000546.6(TP53):c.1096T>G (p.Ser366Ala)

gnomAD frequency: 0.00004  dbSNP: rs17881470

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991137	SCV001142528	benign	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.1096T>G variant in TP53 is a missense variant predicted to cause substitution of serine by alanine at amino acid 366 (p.Ser366Ala). 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 contributors: SCV000214696.6). 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 = 0.1186; 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: BS2, BS3, BP4. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)
GeneDx	RCV001704037	SCV000211768	likely benign	not provided	2020-08-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 18511570, 12672316, 29467486, 19416725, 31422574, 21343334, 17606709, 19933256, 28861920, 15659650, 24729566, 24256616, 25503501, 30352134, 29844874, 31016814, 30840781, 33300245)
Ambry Genetics	RCV000161039	SCV000214696	likely benign	Hereditary cancer-predisposing syndrome	2019-09-30	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	RCV000991137	SCV000254624	likely benign	Li-Fraumeni syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122179	SCV000697425	benign	not specified	2021-04-25	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.1096T>G (p.Ser366Ala) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249484 control chromosomes, predominantly at a frequency of 0.00023 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.1096T>G has been reported in the literature in individuals affected with Li-Fraumeni Syndrome, breast- and bladder cancer, without strong evidence for causality (e.g. Monti_2007, Lalloo_2006, Bougeard_2008, Maxwell_ 2014); however, it was also found in healthy- or cancer-free controls as a secondary finding (e.g. Bodian_2014, de Andrade_2017, Kraemer_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (TP53 c.742C>T, p.Arg248Trp), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Monti_2011, Shinmen_2009). Six 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 benign (n=1)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000161039	SCV000910821	likely benign	Hereditary cancer-predisposing syndrome	2015-12-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000989697	SCV001140236	benign	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798387	SCV002042822	uncertain significance	Breast and/or ovarian cancer	2020-08-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001704037	SCV002046121	likely benign	not provided	2021-12-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000161039	SCV002530425	likely benign	Hereditary cancer-predisposing syndrome	2021-03-13	criteria provided, single submitter	curation
ITMI	RCV000122179	SCV000086394	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356420	SCV001551582	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Ser366Ala variant was identified in 2 of 1112 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was present in 3 of 1362 control chromosomes (frequency: 0.002) from healthy individuals (Lalloo 2006, Maxwell 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs17881470 as With Uncertain significance allele), ClinVar (Likely benign, reviewed by expert panel. Classified as LB by ClinGen, GeneDx, Ambry, Invitae, Color. Classified as B by Mendelics), Cosmic (previously reported in Acute lymphoblastic leukemia and Squamous cell carcinoma), LOVD 3.0 (as probably does not affect function), IARC TP53 Database, and UMD TP53 Mutation Database.  The variant was identified in control databases in 15 of 249484 chromosomes (0 homozygous) at a frequency of 0.00006012, and was observed at the highest frequency in the Latino population in 8 of 34410 chromosomes (freq: 0.0002325) (Genome Aggregation Database March 6, 2019, v2.1.1) The p.Ser366 residue is conserved in mammals, though computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Ser366Ala variant was found to have a mean residual transactivation activity of a luciferase reporter gene at 101% relative to the wild type allele and was classified as a partial deficiency allele (Monti 2011). Another study showed that phosphorylation of Ser366 was markedly reduced in CHEK2-knockdown cells and that phosphorylation of Ser366 is activated by irradiation-induced DNA damage (Ou 2005). The phosphorylation of at least one but not all of three residues in p53, including S366, is essential for p53 regulation by some 14-3-3 isoforms (Rajagopalan 2010). Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4) (ClinGen ClinVar submission, SCV001142528.1).  In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003965030	SCV004777191	likely benign	TP53-related disorder	2024-01-04	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).