ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.28G>A (p.Val10Ile)

gnomAD frequency: 0.00004  dbSNP: rs535274413
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000203717 SCV001142535 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.28G>A; p.Val10Ile 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 RCV000235217 SCV000149626 likely benign not provided 2020-10-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19651601, 24811890, 25186627, 30287823, 30840781, 30224644, 33300245)
Ambry Genetics RCV000115717 SCV000184102 likely benign Hereditary cancer-predisposing syndrome 2018-09-14 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.
Invitae RCV000203717 SCV000260029 uncertain significance Li-Fraumeni syndrome 2023-12-04 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 10 of the TP53 protein (p.Val10Ile). This variant is present in population databases (rs535274413, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 35264596). ClinVar contains an entry for this variant (Variation ID: 127806). 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, 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.
Counsyl RCV000662410 SCV000784841 uncertain significance Li-Fraumeni syndrome 1 2017-01-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000235217 SCV000884715 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing The TP53 c.28G>A;p.Val10Ile variant has been shown to function similarly to wild type in at least some functional studies (Kato 2003, Shiraishi 2004). The variant is listed in the ClinVar database (Variation ID: 127806) and the dbSNP variant database (rs535274413) with an allele frequency of 0.003258 percent (8/245572 alleles) in the Genome Aggregation Database. The amino acid at this position is weakly conserved across species and computational algorithms (Align GVGD, PolyPhen2, SIFT) predict this variant is tolerated, although the amino acid is located in the transactivation domain (Bode 2004). Considering available information, there is insufficient evidence to classify the variant with certainty. If this variant is later determined to be pathogenic, this individual would be at increased risk for development of hereditary cancers (OMIM#191170). References: Bode AM and Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004 Oct;4(10):793-805. Kato S et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Shiraishi K et al. Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. J Biol Chem. 2004 Jan 2;279(1):348-55.
Color Diagnostics, LLC DBA Color Health RCV000115717 SCV000911076 likely benign Hereditary cancer-predisposing syndrome 2015-04-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781916 SCV000920321 uncertain significance not specified 2022-12-01 criteria provided, single submitter clinical testing Variant summary: TP53 c.28G>A (p.Val10Ile) results in a conservative amino acid change located in the p53 transactivation domain (IPR013872) of 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 3.2e-05 in 250780 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.28G>A has been reported in the literature in at least three individuals affected with breast cancer (e.g. Tung_2016, Akcay_2021), two of whom also carried a co-occurring a pathogenic variant (CDH1 c.521dupA, p.Asn174LysfsX25) (Tung_2016), providing support for a benign role. The variant was also found in unaffected East Asian and Hispanic control individuals (Momozawa_2018, Weitzel_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications reporting experimental evidence evaluating an impact on protein function show little to no damaging effect of this variant, including evidence from yeast assays that the variant retains transactivation capacity comparable to wild-type TP53 (e.g. Kato_2003, Giacomelli_2018). Ten submitters, including the ClinGen TP53 Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either likely benign (n=5) or VUS (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000989729 SCV001140272 benign Squamous cell carcinoma of the head and neck 2023-08-22 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115717 SCV002530443 likely benign Hereditary cancer-predisposing syndrome 2021-09-13 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000662410 SCV004017904 uncertain significance Li-Fraumeni syndrome 1 2023-04-12 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.
PreventionGenetics, part of Exact Sciences RCV003905099 SCV004719441 likely benign TP53-related disorder 2021-04-16 criteria provided, single submitter 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).

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