ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1096T>G (p.Ser366Ala) (rs17881470)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000991137 SCV001142528 likely benign Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, 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). In summary, TP53 c.1096T>G; p.Ser366Ala meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.
GeneDx RCV000122179 SCV000211768 likely benign not specified 2018-02-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000161039 SCV000214696 likely benign Hereditary cancer-predisposing syndrome 2019-09-30 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000991137 SCV000254624 likely benign Li-Fraumeni syndrome 2020-12-03 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 Health, Inc 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
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.