Variant classification summary

NM_000546.5:c.623A>C

TP53 · NP_000537.3:p.(Asp208Ala) · NM_000546.5

GRCh37: chr17:7578226 T>G · GRCh38: chr17:7674908 T>G

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Asp208Ala)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, below the VCEP's <0.003% threshold.

2

PP3 moderate: the TP53 VCEP assigns c.623A>C to Class C65 with BayesDel 0.596355 and PP3_moderate.

Final determination: Under the TP53 VCEP Version 2.4 point-based framework, PM2 supporting contributes 1 point and PP3 moderate contributes 2 points; the total of 3 points falls within the -1 to 5 point VUS range.

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	Not applicable: c.623A>C is a missense substitution at p.Asp208Ala, whereas the TP53 PVS1 rule covers null, splice-site, frameshift, nonsense, and copy-number variants.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: p.Asp208Ala has SpliceAI max delta 0.01, but no qualifying pathogenic or likely pathogenic same-amino-acid comparator was identified.	cspec clinvar spliceai pm5_candidates
PS2	Not assessed	Not assessed: no documented de novo event, parental testing, or proband cancer points are available to reach the VCEP's 1-point PS2 Supporting threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: the governing D208A row assigns No evidence, with only 1 of 3 available non-Kato assays showing LOF and no qualifying Moderate or Supporting path.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec PMID:12826609
PS4	Not assessed	Not assessed: no proband phenotype or PS4 point total is available to compare with the VCEP's 1-1.5, 2-3.5, 4-7.5, or >=8 thresholds.	cspec vcep_ps4_points_table
PM1	Not assessed	Not assessed: D208 is outside the six listed hotspot codons, while the required same-amino-acid somatic count for the reported hotspot is unavailable.	cspec
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed allele frequency 0 versus the <0.003% PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the TP53 VCEP explicitly marks PM4 as Not Applicable for this specification.	cspec
PM5	Not assessed	Not assessed: residue 208 has zero usable same-residue comparator variants, so the VCEP pathogenicity and Grantham requirements cannot be tested.	cspec pm5_candidates spliceai
PM6	N/A	Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable for this specification.	cspec
PP1	Not assessed	Not assessed: no documented cosegregation meioses are available to meet the VCEP minimum of 3-4 meioses for PP1 Supporting.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable.	cspec
PP3	Met	Met at moderate strength: the VCEP table pre-assigns PP3_moderate for c.623A>C with BayesDel 0.596355 (Class C65).	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: VAF, multigene-panel detection, and required clinical exclusions are unavailable for comparison with the VCEP's PP4 rule.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of PP5.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no qualifying ancestry-group FAF reaches the 0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no qualifying ancestry-group FAF lies between 0.03% and 0.1%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying single-source count of unrelated female carriers aged at least 60 years without cancer is available.
BS3	Not met	Not met: the governing D208A row assigns No evidence because Kato is non-functional and Giacomelli reports LOF.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec PMID:12826609
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are available to demonstrate the VCEP's BS4 lack-of-segregation rule.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because truncating variants account for only a portion of TP53 disease-causing variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 not applicable, regardless of the specified trans or phase-unknown observation scenarios.	cspec
BP3	N/A	Not applicable: the TP53 VCEP explicitly marks BP3 as Not Applicable for this specification.	cspec
BP4	Not met	Not met: BP4 is explicitly barred for the VCEP Class C65 row, despite BayesDel 0.596355 and SpliceAI maximum delta 0.01.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: the TP53 VCEP marks BP5 as not applicable regardless of alternate molecular-basis evidence.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of BP6.	cspec
BP7	N/A	Not applicable: c.623A>C is an exonic missense variant, whereas BP7 applies only to synonymous or intronic variants.	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.