Variant classification summary

NM_000546.6:c.797G>T

TP53 · NP_000537.3:p.(Gly266Val) · NM_000546.6

GRCh37: chr17:7577141 C>A · GRCh38: chr17:7673823 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly266Val)

gnomAD AF

0.0 (v2.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): allele frequency 0 in gnomAD v2.1 (0/248,882 alleles), absent from gnomAD v4.1 and gnomAD-Canada, meeting the <0.003% threshold.

2

PP3 (Moderate): Align-GVGD Class C65 and BayesDel score 0.599005 meet the VCEP PP3_Moderate threshold (BayesDel >= 0.16).

3

Final classification: Uncertain Significance (VUS) under the TP53 VCEP v2.4 point framework (3 points, Rule3: -1 to 5).

Final determination:

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: this is a missense substitution (p.Gly266Val), not a null variant such as nonsense, frameshift, or splice-site change.	cspec
PS1	Not assessed	Not assessed: no alternative nucleotide change producing p.Gly266Val with an established pathogenic classification was available as a comparator.	cspec
PS2	Not assessed	Not assessed: no parental testing or de novo occurrence data were available for the proband.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not assessed	Not assessed: no functional assay result specific to p.Gly266Val was available; the only VCEP worksheet row covers a different substitution (p.Gly266Ala).	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:30224644 PMID:29979965
PS4	Not assessed	Not assessed: no eligible proband observations or case-control enrichment data for p.Gly266Val were available.	cspec
PM1	Not assessed	Not assessed: codon 266 is not among the TP53 VCEP hotspot codons (175, 245, 248, 249, 273, 282).	cspec PMID:27328919
PM2	Met	Met (Supporting): allele frequency is 0 in gnomAD v2.1 (0/248,882 alleles) and the variant is absent from gnomAD v4.1, below the 0.003% PM2 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is not used for TP53 under VCEP v2.4, which applies only to recessive or X-linked disorders.	cspec
PM4	N/A	Not applicable: PM4 is not used for TP53 under VCEP v2.4, and this missense causes no protein length change.	cspec
PM5	Not assessed	Not assessed: no other codon 266 missense variant with an established pathogenic classification was available as a comparator.	cspec
PM6	N/A	Not applicable: TP53 VCEP v2.4 dropped PM6, directing de novo evidence to PS2 only.	cspec
PP1	Not assessed	Not assessed: no affected relatives or cosegregation data were available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: PP2 is not used for any TP53 variant under VCEP v2.4.	cspec
PP3	Met	Met (Moderate): Align-GVGD Class C65 and BayesDel score 0.599005 meet the VCEP PP3_Moderate threshold (BayesDel >= 0.16).	vcep_pp3_bp4_codes cspec bayesdel spliceai
PP4	Not assessed	Not assessed: no blood-test variant allele fraction or testing-context data were available for this low-VAF rule.	cspec
PP5	Not met	Not met: the ClinVar record has no expert-panel submissions; the lone pathogenic assertion comes from a single laboratory.	clinvar cspec
BA1	Not met	Not met: the variant is absent from population databases (0/248,882 gnomAD v2.1 alleles), far below the 0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: allele frequency is 0 in gnomAD, below the 0.03% BS1 frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no data on unrelated cancer-free carriers aged 60 or older were available.	cspec
BS3	Not assessed	Not assessed: no functional assay result specific to p.Gly266Val was available to assess a benign effect.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:30224644 PMID:29979965
BS4	Not assessed	Not assessed: no family members tested and found not to carry the variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: BP1 is not used for any TP53 variant under VCEP v2.4.	cspec
BP2	N/A	Not applicable: BP2 is not used for TP53 under the VCEP v2.4 framework.	cspec
BP3	N/A	Not applicable: BP3 is not used under the TP53 VCEP, and this is a missense substitution, not an in-frame indel.	cspec
BP4	Not met	Not met: BayesDel 0.599005 is far above the benign threshold, and BP4 is mutually exclusive with the assigned PP3_Moderate code.	vcep_pp3_bp4_codes cspec bayesdel
BP5	N/A	Not applicable: BP5 is not used in the TP53 VCEP v2.4 specification.	cspec
BP6	Not met	Not met: the ClinVar record has no expert-panel benign or likely benign classification.	clinvar cspec
BP7	N/A	Not applicable: this is a missense variant, not synonymous or intronic, so BP7 does not apply.	cspec

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