ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.245C>T (p.Pro82Leu) (rs534447939)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000205955 SCV001142533 likely benign Li-Fraumeni syndrome 2019-08-28 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.245C>T; p.Pro82Leu 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 RCV000213048 SCV000211777 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing This variant is denoted TP53 c.245C>T at the cDNA level, p.Pro82Leu (P82L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was shared by three of five women in a breast cancer kindred that did not demonstrate linkage to the TP53 locus and for which studied tumors did not demonstrate TP53 loss of heterozygosity (Sun 1996). While this variant has been reported to have functional transcriptional activation and normal DNA binding activity in multiple functional studies (Monti 2011, Bisio 2013, IARC TP53 database, Malcikova 2010), this residue is part of a PXXP motif in the SH3 domain, a region demonstrated to impact growth arrest in a transactivation-independent manner (Ruaro 1997). Deletion of the TP53 Pro82 residue or replacement with an Isoleucine (Pro82Ile) impacted autophosphorylation of the TP53 Ser20 residue and impaired Chk2 interaction post-irradiation (Berger 2005). Given that Leucine and Isoleucine share similar structural and chemical properties, Pro82Leu may behave in a similar manner, however assays to interrogate this have not been performed to date. TP53 Pro82Leu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Pro82Leu occurs at a position that is not conserved and is located in the SH3 domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, we consider TP53 Pro82Leu to be a variant of uncertain significance.
Ambry Genetics RCV000161047 SCV000215716 likely benign Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Insufficient or conflicting evidence;Intact protein function observed in appropriate functional assay(s)
Invitae RCV000205955 SCV000259808 uncertain significance Li-Fraumeni syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 82 of the TP53 protein (p.Pro82Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs534447939, ExAC 0.006%). This variant has been observed in individual(s) with breast cancer (PMID: 8710380, 28202063). ClinVar contains an entry for this variant (Variation ID: 182946). Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 21343334, 17606709, 20128691, 24256616, 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 Health, Inc RCV000161047 SCV000911119 likely benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
Mendelics RCV000989726 SCV001140269 benign Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001250438 SCV001424812 uncertain significance Li-Fraumeni syndrome 1 2019-05-20 criteria provided, single submitter clinical testing The c.245C>T variant was identified in three of five women with breast cancer in a late-onset breast cancer family (Sun 1996). The c.245C>T variant has an allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355900 SCV001550917 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.Pro82Leu variant was not identified in the literature in an affected population. The variant was also identified in dbSNP (ID: rs534447939) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; as uncertain significance by GeneDx and Ambry Genetics), Cosmic (9x in skin, soft tissue, salivary gland, large intestine, haematopoietic and lymphoid tissue, upper aerodigestive tract), LOVD 3.0, and the IARC TP53 Database (7x in somatic and 2x in germline count). The variant was not identified in the GeneInsight-COGR database. The variant was identified in control databases in 5 of 246174 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15290 chromosomes (freq: 0.00007), European in 3 of 111654 chromosomes (freq: 0.00003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The variant showed a DNA binding activity similar to wild type p53 and did not show dominant negative activity (Malcikova 2010, Monti 2011). The p.Pro82 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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