TP53 c.847C>T, p.Arg283Cys
NM_000546.5:c.847C>T
COSMIC ID: COSM10911, COSM6923587
Likely Pathogenic
PS3_Strong (functional LOF) and PM5_Moderate (novel pathogenic residue) support a Likely Pathogenic classification for TP53 R283C; no benign or additional pathogenic criteria apply.
ACMG/AMP Criteria Applied
PS3
PM5
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.5:c.847C>T
Protein Change
R283C
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 283 in gene TP53
Alternate Identifiers
COSM10911, COSM6923587
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.847C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00743%
Rare
Highest in Population
Remaining individuals
0.0138%
Low Frequency
Global: 0.00743%
Remaining individuals: 0.0138%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282828Alt: 21Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00743%, 21/282828 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0138%, 1/7228 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Uncertain Significance (VUS)
Based on 16 submitter reviews in ClinVar
Submitter Breakdown
7 VUS
9 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
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.
Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251440 control chromosomes. The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05).c.847C>T has been reported in the literature in patients with chronic lymphocytic leukemia, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Keller_2004, Manoukian_2007, Melhem-Bertrandt_2012, Schulz_2012, Mitchell_2013, Wang_2013, Yurgelun_2015, Mai_2017, Momozawa_2018, Young_2018, Abe_2019, Tsaousis_2019, Rodriguez-Balada_2020, Shin_2020). Manoukian et al (2007) reported one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma and carried TP53 c.847C>T variant along with a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in the patients family, as it was absent in an astrocytoma patient. Lack of co-segregation with disease was also evident in the families of two probands affected with breast cancer (Fostira_2020) and one proband affected with glioblastoma multiforme who also carried a pathogenic MLH1 variant (c.333_334delTC, p.His112CysfsX9) depicted by the authors as the main cause of cancer (Stajkovska_2019). Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Monti_2011, Pekova_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al (2003). ClinVar contains an entry for this variant (Variation ID: 127824). Based on the evidence outlined above, the variant was classified as likely benign.
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (9 clinical laboratories) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Likely Benign
ClinGen TP53 Variant Curation Expert Panel, ClinGen
COSMIC ID
COSM10911, COSM6923587
Recurrence
30 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 283 in gene TP53
Functional Summary
Loss-of-Function
The TP53 R283C variant has been functionally characterized and is associated with a likely loss-of-function effect. It resides within the DNA-binding domain of the TP53 protein and exhibits reduced transactivation activity. Additionally, the corresponding mouse variant (R277C) shows decreased ability to inhibit TgfB-induced epithelial-to-mesenchymal transition in culture, supporting a damaging effect.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.74
0.74
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 3.91polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PVS1 applies to null variants (nonsense, frameshift, canonical splice, initiation codon, or multi‐exon deletions predicted to undergo NMD)'. The variant is a missense change (R283C). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant'. R283C is a novel amino acid change at codon 283. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS2 requires de novo occurrence with parental testing, scored by points system'. No de novo or parental testing data are provided. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines: 'PS3_Strong: Non‐functional on Kato et al. data AND loss of function (LOF) on another assay'. The variant demonstrates reduced transactivation activity (Kato‐type assay) and decreased inhibition in a mouse EMT assay. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS4 requires proband case‐control or segregation points totaling ≥2'. No case or control data or proband point tally is available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM1 applies to missense variants at TP53 hotspots codons 175, 245, 248, 249, 273, 282'. R283C falls outside these hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM2_Supporting requires allele frequency <0.00003 in gnomAD'. The variant MAF is 0.0000743 (0.00743%), above the threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG: 'PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders'. TP53 is dominant and no trans data are provided. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG: 'PM4 applies to protein length changes (in‐frame indels or stop‐loss)'. R283C is a missense change. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines: 'PM5_Moderate: Missense variant at an amino acid residue where one different missense variant previously determined to be pathogenic according to the TP53 VCEP’s specifications has been seen before'. A different pathogenic change at codon 283 exists. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG: 'PM6 applies to assumed de novo cases without parental confirmation'. No de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP1 requires cosegregation evidence in 3–4 meioses (Supporting) or higher'. No family segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG: 'PP2 applies when missense variants are rare causes of disease in genes where such changes are not a common mechanism'. TP53 disease mechanism is frequently missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP3 requires a BayesDel ≥0.16 and SpliceAI <0.2'. BayesDel score is not provided and in silico predictions are mixed. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG: 'PP4 requires a highly specific phenotype or family history'. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG: 'PP5 applies to reports from reputable sources without primary data'. ClinGen TP53 Expert Panel has called this variant Likely Benign, conflicting with pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BA1 requires FAF ≥0.001 in any continental gnomAD subpopulation'. Variant MAF 0.0000743 <0.001. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS1 requires FAF ≥0.0003 but <0.001 in any gnomAD subpopulation'. Variant MAF 0.0000743 <0.0003. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS2 requires ≥8 unaffected older females without cancer'. No such data are provided. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS3_Strong applies to functional data showing no loss of function'. Functional studies show loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS4 applies to lack of segregation in multiple affected'. No segregation data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG: 'BP1 applies when only truncating variants cause disease'. TP53 disease mechanism often involves missense changes. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG: 'BP2 applies to observed in trans with a pathogenic variant in recessive disorders'. Not applicable for dominant TP53. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG: 'BP3 applies to in‐frame indels in repetitive regions'. This is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP4_Moderate requires BayesDel ≤−0.008 and SpliceAI <0.2'. BayesDel is unavailable and in silico predictions are mixed. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG: 'BP5 applies to variant found in a case with alternate molecular cause'. No such data are provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG: 'BP6 applies to untrusted assertions of benignity'. Not used per ClinGen recommendations. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP7 applies to synonymous or intronic variants with no splicing impact'. This is a missense change. Therefore, this criterion is not applied.