Variant classification summary

NM_000546.6:c.845G>A

TP53 · NP_000537.3:p.(Arg282Gln) · NM_000546.6

GRCh37: chr17:7577093 C>T · GRCh38: chr17:7673775 C>T

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg282Gln)

gnomAD AF

5.576360198171449e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.845G>A (p.Arg282Gln) variant has been reported in ClinVar with conflicting germline classifications and is also described in somatic cancer literature at a recurrent TP53 hotspot residue.

2

This variant is rare in population databases, with an allele frequency of 5.58e-06 in gnomAD v4.1 and 3.98e-06 in gnomAD v2.1, which supports PM2 at Supporting strength under the TP53 VCEP thresholds.

3

Available functional evidence is mixed and does not meet TP53 VCEP criteria for either damaging or benign functional evidence; the TP53 functional worksheet assigns p.Arg282Gln as 'No evidence' for PS3/BS3.

4

Computational evidence supports a deleterious effect because the TP53 VCEP in silico worksheet assigns PP3 to c.845G>A, BayesDel is 0.477696, REVEL is 0.887, and SpliceAI predicts no meaningful splice impact.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 4, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, not a nonsense, frameshift, canonical splice, or other TP53 null variant, so PVS1 does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No verified TP53 VCEP pathogenic or likely pathogenic variant with the same amino acid change was identified for PS1 assessment.	cspec clinvar
PS2	Not assessed	No variant-specific confirmed de novo observation with the TP53 point-based requirements was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:10864200
PS3	Not met	TP53 VCEP functional data do not support PS3 for this variant. The TP53 functional worksheet entry for p.Arg282Gln is assigned 'No evidence', indicating the available assay results do not meet the VCEP threshold for damaging functional evidence.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:11896595 PMID:11920959 PMID:18453682
PS4	Not assessed	Although PM2_Supporting is met, no variant-specific germline case series with sufficient TP53 PS4 point scoring were identified, so PS4 cannot be assigned.	cspec vcep_ps4_points_table PMID:10864200 clinvar
PM1	Met	This missense variant affects TP53 codon 282, one of the codons explicitly designated by the TP53 VCEP as a mutational hotspot for PM1 at Moderate strength.	cspec PMID:18453682 PMID:26619011
PM2	Met	This variant is rare in population databases. In gnomAD v4.1, the overall allele frequency is 5.58e-06, which is below the TP53 PM2 threshold of 3.0e-05, and the highest observed subpopulation frequency is 2.23e-05, which is below the 4.0e-05 subpopulation threshold. gnomAD v2.1 shows 1 allele among 251444 alleles (3.98e-06).	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not used in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not used in the TP53 VCEP framework.	cspec
PM5	Not assessed	No fully verified same-residue TP53 VCEP pathogenic or likely pathogenic comparator set was established from the reviewed materials, so PM5 was not assigned.	cspec pm5_candidates clinvar
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No variant-specific segregation data with enough informative meioses were identified to support PP1.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not used in the TP53 VCEP framework.	cspec
PP3	Met	Computational evidence supports a deleterious effect. The TP53 VCEP PP3/BP4 spreadsheet assigns PP3 to c.845G>A; BayesDel is 0.477696, above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.887, and SpliceAI shows no predicted splice effect (max delta score 0.00).	cspec vcep_pp3_bp4_codes bayesdel revel spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	No low-variant-allele-fraction blood observation or related mosaicism evidence meeting the TP53 PP4 requirements was identified.	cspec
PP5	N/A	PP5 is not used in the TP53 VCEP framework.	cspec
BA1	Not met	Population frequency does not meet the TP53 BA1 threshold. The highest available filtering allele frequency remains well below 0.001.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Population frequency does not meet the TP53 BS1 threshold. The observed population frequencies are below the TP53 BS1 cutoff of 0.0003.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No single-source dataset showing the required number of unrelated females age 60 years or older without cancer was identified for this variant.	cspec clinvar
BS3	Not met	TP53 VCEP functional data do not support BS3 for this variant. The TP53 functional worksheet entry for p.Arg282Gln is assigned 'No evidence', so the available assays do not meet the VCEP threshold for benign functional evidence.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:11896595 PMID:11920959
BS4	Not assessed	No variant-specific lack-of-segregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not used in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not used in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not used in the TP53 VCEP framework.	cspec
BP4	Not met	Computational evidence does not support BP4. The TP53 VCEP PP3/BP4 spreadsheet assigns PP3 rather than BP4 to c.845G>A, and BayesDel is 0.477696, which is above the TP53 pathogenic threshold of 0.16.	cspec vcep_pp3_bp4_codes bayesdel spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	BP5 is not used in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not used in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic variant.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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