Variant classification summary

NM_000546.5:c.319T>C

TP53 · NP_000537.3:p.(Tyr107His) · NM_000546.5

GRCh37: chr17:7579368 A>G · GRCh38: chr17:7676050 A>G

Gene: TP53 Transcript: NM_000546.5

Final call

Benign

BS1_Strong BS3_Supporting BP4_Supporting BP6_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Tyr107His)

gnomAD AF

5.5813192006062555e-05 (v4.1)

ClinVar

Benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.319T>C (p.Tyr107His) variant has been observed in somatic cancers with 2 COSMIC observations and has been reported in ClinVar with a Benign expert-panel classification from the ClinGen TP53 Variant Curation Expert Panel.

2

This variant is present in gnomAD above the TP53 PM2 threshold and within the TP53 BS1 range, with grpmax filtering allele frequencies of 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1.

3

In the TP53 VCEP functional worksheet, Y107H is recorded as partially functional with no loss of function in other eligible assay columns, supporting BS3_Supporting and arguing against PS3.

4

TP53-specific in silico assessment assigns BP4 for c.319T>C; BayesDel is 0.020196, SpliceAI predicts no splice impact with a max delta score of 0.00, and the available computational evidence does not support PP3.

Final determination: Under the TP53 ClinGen VCEP v2.4.0 Tavtigian point-based framework, BS1_Strong (-4), BS3_Supporting (-1), BP4_Supporting (-1), and BP6_Supporting (-1) sum to -7 points, which classifies the variant as Benign.

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 variant is a missense substitution, TP53 p.(Tyr107His), and does not fall into the TP53 null-variant categories used for PVS1. Available splice evidence does not support a loss-of-function splicing mechanism, with SpliceAI max delta score 0.00.	pvs1_gene_context pvs1_variant_assessment spliceai vcep_pvs1_flowchart
PS1	Not assessed	No same-amino-acid pathogenic TP53 comparator was confirmed for this codon, so PS1 was not assessed.	cspec
PS2	Not assessed	No confirmed de novo observation with the TP53-specific clinical details and parental confirmation required for PS2 was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	TP53 functional evidence does not support a damaging loss-of-function interpretation for this variant. In the TP53 functional worksheet, Y107H is recorded as partially functional with no loss of function in other eligible assay columns and is assigned BS3_Supporting rather than a PS3 code.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PS4	Not met	Available evidence does not support PS4. This variant does not meet the TP53 PM2_Supporting rarity prerequisite because it is present in gnomAD above the PM2 threshold, and no qualifying Li-Fraumeni syndrome point-based case enrichment data were identified.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not support PM1. Codon 107 is not one of the TP53 codons specified for automatic PM1 application, Cancer Hotspots evidence for this residue was uncertain, and only 2 somatic observations were identified in COSMIC, which does not establish a TP53 hotspot-based PM1 determination.	cspec hotspots
PM2	Not met	This variant is too common for TP53 PM2_Supporting. Its total allele frequency is 0.000120 in gnomAD v2.1 and 0.0000558 in gnomAD v4.1, both above the TP53 PM2 threshold of less than 0.00003, and multiple African/African American alleles are present above the single-group threshold of less than 0.00004.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not applicable in the TP53 VCEP framework.	cspec
PM5	Not assessed	PM5 was not assessed because no verified same-residue TP53 pathogenic or likely pathogenic comparator set was confirmed for codon 107 in the reviewed materials.	cspec pm5_candidates
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to show co-segregation of this variant with Li-Fraumeni syndrome-associated disease across informative meioses.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Not met	Computational evidence does not support PP3 for this TP53 missense variant. The TP53 VCEP in silico worksheet assigns BP4, not PP3, with BayesDel score 0.020196 below the TP53 PP3 threshold of 0.16 and SpliceAI max delta score 0.00 showing no predicted splice effect.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No qualifying low-variant-allele-fraction constitutional mosaic observations were identified for this variant, so TP53-specific PP4 was not assessed.	cspec
PP5	N/A	PP5 is not applicable in this framework.	cspec
BA1	Not met	This variant does not meet TP53 BA1 because the observed filtering allele frequency does not reach the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant meets TP53 BS1 because its filtering allele frequency is above the BS1 threshold of 0.0003 but below the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1, with the highest population frequency in African/African American individuals.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No single-source dataset of unaffected older female carriers was identified to support BS2.	cspec
BS3	Met	Published TP53 functional evidence supports BS3_Supporting for this variant. In the TP53 functional worksheet, Y107H is listed as partially functional with no loss of function in other eligible assay columns, and the pre-assigned TP53 VCEP code is BS3_Supporting.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
BS4	Not assessed	No family data were identified to demonstrate lack of segregation with Li-Fraumeni syndrome-associated disease.	cspec
BP1	N/A	BP1 is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework.	cspec
BP4	Met	Computational evidence supports TP53 BP4. The TP53 VCEP in silico worksheet assigns BP4 for c.319T>C, the BayesDel score is 0.020196, which is below the TP53 PP3 threshold of 0.16 and above the BP4_Moderate cutoff of -0.008, and SpliceAI predicts no splice effect with a max delta score of 0.00.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	BP7 is not applicable 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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