TP53 c.917G>A, p.Arg306Gln
NM_000546.6:c.917G>A
COSMIC ID: COSM6845292, COSM6982167
Variant of Uncertain Significance (VUS)
This TP53 missense variant R306Q has only a single supporting PM2 population‐frequency evidence and lacks other supporting or benign evidence under VCEP guidelines, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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_000546.6:c.917G>A
Protein Change
R306Q
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 306 in gene TP53
Alternate Identifiers
COSM6845292, COSM6982167
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.917G>A
Active Tracks
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251484Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251484 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34592 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
8 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
9 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (8)
The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as variant of uncertain significance in the context of famiial breast cancer. Loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in one family, which provides evidence for pathogenicity. Some TP53 missense variants have been associated with somewhat increased risk of breast cancer, but do not cause the high cancer risk associated with truncating TP53 variants (Giacomazzi et al., 2014, PMID:24936644; Arcand et al., 2015, PMID:25925845; Zick et al., 2016, PMID:27866339). Exact breast cancer penetrance for these variants has not been established. For the TP53 p.Arg306Gln variant, family co-segregation analysis assuming low penetrance gives a likelihood ratio of 0.34 using the Thompson et al. cosegregation method (PMID:12900794). This likelihood ratio is less than one, indicating that the variant is less likely to be associated with breast cancer risk. The TP53 p.Arg306Gln variant has not previously been reported in ClinVar. It is at a moderately conserved genomic position. A modest increase in breast cancer risk due to this variant cannot be entirely excluded. This variant is considered a variant of uncertain significance in the context of breast cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Variant summary: TP53 c.917G>A (p.Arg306Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.917G>A has been reported in the literature in individuals affected breast- and ovarian cancer (e.g. Blanco_2010, Tsai_2019), and with various tumor phenotypes that belong to the Li-Fraumeni Syndrome tumor spectrum (e.g. Fenwarth_2020, Tian_2022), however it was also reported in unaffected controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be non- functional based on transcriptional activity in yeast (Kato_2003). However, a loss-of-function saturation mutagenesis screen performed in in human cell lines indicated that this missense doesn't substantially affect TP53 function (Giacomelli_2018). In addition, a multifactorial probability model predicted this variant to be a VUS (Fortuno_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19930417, 30374176, 32554555, 33471991, 35033608, 12826609, 30224644, 34273903). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 19930417 (2010)). Experimental results on protein function were inconclusive (PMIDs: 30352134 (2019), 30224644 (2018), 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
The p.R306Q variant (also known as c.917G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 917. The arginine at codon 306 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an ovarian cancer patient and in a pediatric AML patient (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6; Fenwarth L et al. Haematologica, 2021 03;106:908-912). This variant was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was classified as likely benign by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This missense variant replaces arginine with glutamine at codon 306 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant displays partial function in yeast transcription transactivation assays and is functional in human cell growth suppression assays (PMID: 12826609, 30224644). This variant has not been reported in individuals affected with lung, apendiceal and ovarian cancers (PMID: 19930417, 35033608) but also in unaffected individuals (PMID: 33471991). This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
172
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (172 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 306 in gene TP53
Functional Summary
The TP53 R306Q variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.764
0.764
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
Yes
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 3.94polyphen_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, the rule for PVS1 is: "PVS1 applies to null variants in TP53 (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon) predicted to undergo NMD upstream of p.Lys351." The evidence for this variant shows it is a missense change (R306Q), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant." The evidence for this variant shows no prior pathogenic R306 substitutions reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Confirmed de novo variant with appropriate family studies." No de novo occurrence data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Functional assay supportive of damaging effect (e.g., non‐functional on Kato et al. AND LOF on another assay)." The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Statistical enrichment of the variant in affected individuals (proband points)." No case‐level or cohort data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Missense variants at hotspot codons 175, 245, 248, 249, 273, or 282 (Moderate), or with 2–9 somatic occurrences for the same amino acid (Supporting)." The evidence for this variant shows codon 306 is not in the specified hotspot list and has zero somatic occurrences. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent or extremely low frequency in controls (gnomAD AF <0.00003)." The evidence for this variant shows a gnomAD MAF of 0.00000398 (0.000398%), which is below the 0.00003 threshold. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." TP53-associated conditions are dominant, and no trans data exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes such as in‐frame indels or stop-loss variants." This variant is a missense change without length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense variant at a residue where ≥2 different missense variants are pathogenic (Strong), or ≥1 (Moderate/Supporting)." The evidence shows no reported pathogenic variants at codon 306. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation." No de novo or maternity/paternity information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Cosegregation in multiple affected family members (Supporting to Strong)." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." TP53 does have known pathogenic missense and benign variation, and no specific data on benign missense rate are provided. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Computational evidence supporting deleterious effect (BayesDel ≥0.16 or aGVGD C25–C65)." No BayesDel or aGVGD scores are provided. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Phenotype specificity and VAF observations." No patient phenotype or VAF data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." ClinVar entries report this variant as VUS, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency ≥0.001." The evidence shows allele frequency is 0.00000398, below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filtering allele frequency ≥0.0003 but <0.001." The evidence shows allele frequency is 0.00000398, below this range. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observation in ≥2–8 healthy older females." No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Functional assays demonstrate no loss of function." No functional data exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." TP53 has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis/trans with a pathogenic variant for a dominant gene." No such data exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indel in repetitive region." This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Computational evidence supporting benign effect (BayesDel <0.16 and SpliceAI <0.2)." BayesDel is not provided, so BP4 cannot be applied. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." No such alternate explanation is provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." No such benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant outside consensus splice sites with no splicing impact." This change is missense. Therefore, this criterion is not applied.