NM_000546.6:c.1123C>A

TP53 · NP_000537.3:p.(Gln375Lys) · NM_000546.6

GRCh37: chr17:7572986 G>T · GRCh38: chr17:7669668 G>T

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM2_Supporting BS3_Strong

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gln375Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The TP53 c.1123C>A (p.Gln375Lys) variant has been observed in somatic cancers in COSMIC (4 occurrences) and has been reported in ClinVar as Likely benign by a single clinical laboratory.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports TP53 PM2 at supporting strength and does not support BA1 or BS1.

In the TP53 VCEP functional worksheet, p.(Gln375Lys) is classified as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code, supporting retained TP53 function.

Computational evidence is mixed: REVEL is 0.339 and BayesDel is -0.143957, the TP53 PP3/BP4 worksheet preliminarily lists BP4_moderate for c.1123C>A, but that worksheet also flags possible splice impact while the case-specific SpliceAI lookup reported a max delta score of 0.00, so PP3 and BP4 were not applied pending review of the discordant splice predictions.

Final determination: BS3_Strong and PM2_Supporting yield a net Tavtigian score of -3, corresponding to Likely Benign under the TP53 VCEP point-based framework.

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.(Gln375Lys), and does not create a nonsense, frameshift, canonical ±1/2 splice, or other null-variant scenario eligible for TP53 PVS1 application.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a different TP53 variant already classified as pathogenic or likely pathogenic under TP53 VCEP specifications.	cspec
PS2	Not assessed	No de novo observations, parental testing results, or phenotype point assignments were identified for this variant, so PS2 cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant. The TP53 functional worksheet lists p.(Gln375Lys) as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned benign functional code rather than PS3.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not met	Although the variant is absent from gnomAD and therefore meets the population prerequisite for TP53 PS4 review, no qualifying proband observations or Li-Fraumeni syndrome point total were identified to support PS4.	cspec gnomad_v2 gnomad_v4 vcep_ps4_points_table
PM1	Not met	This missense variant has been reported 4 times in COSMIC, but no Cancer Hotspots residue row or statistically significant hotspot evidence was identified for codon 375. Available evidence therefore does not support TP53 PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
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	This is a missense variant at codon 375, and TP53 uses classic same-residue PM5 logic. However, no verified TP53 VCEP pathogenic or likely pathogenic same-residue comparator variants were identified in the available evidence, so PM5 cannot be applied.	cspec pm5_candidates
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data, meiosis counts, or multiple affected family observations were identified for this variant, so PP1 cannot be applied.	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	Not assessed	Available computational evidence does not support confident PP3 application. REVEL is 0.339 and local BayesDel is -0.143957, while the TP53 PP3/BP4 worksheet lists c.1123C>A with a preliminary BP4_moderate assignment but flags possible splice-related reconsideration based on a worksheet SpliceAI value of 0.49; in contrast, the case-specific SpliceAI lookup reported a max delta score of 0.00. Because the splicing predictions are discordant, PP3 is not applied.	revel bayesdel spliceai vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 cspec
PP4	Not assessed	No low-variant-allele-fraction blood finding, constitutional mosaicism evidence, or other TP53-specific PP4 qualifying observation was identified, so PP4 cannot be applied.	cspec
PP5	N/A	PP5 is not used in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD and does not reach the TP53 BA1 filtering allele frequency threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD and does not reach the TP53 BS1 filtering allele frequency threshold of 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No source identified 2 or more unrelated older female carriers without cancer, so BS2 cannot be applied.	cspec
BS3	Met	In the TP53 VCEP functional worksheet, p.(Gln375Lys) is listed as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code. These results support retained TP53 function and argue against a damaging effect.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be applied.	cspec
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 assessed	Computational evidence suggests a benign missense effect by BayesDel (-0.143957), and the TP53 PP3/BP4 worksheet preliminarily assigns BP4_moderate for c.1123C>A. However, that same worksheet records a SpliceAI value of 0.49 and advises reconsideration for possible splice impact, while the case-specific SpliceAI lookup reported a max delta score of 0.00. Because TP53 BP4 requires confidence that no splice effect is predicted, BP4 is not applied until this discrepancy is resolved.	bayesdel spliceai vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 cspec revel
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 is a synonymous or intronic splice-prediction criterion and does not apply to this missense variant.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.