Variant classification summary

NM_000546.6:c.1010G>T

TP53 · NP_000537.3:p.(Arg337Leu) · NM_000546.6

GRCh37: chr17:7574017 C>A · GRCh38: chr17:7670699 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PS3 strong PM2 supporting PP5 supporting BP4 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg337Leu)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.1010G>T (p.Arg337Leu; p.R337L) variant has been observed in somatic cancers in COSMIC (COSV52665150, n=69) and has been reported in ClinVar, including a ClinGen TP53 expert panel classification of Likely Pathogenic.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the TP53 PM2_Supporting threshold of less than 0.00003.

3

In TP53 functional data summarized by the TP53 VCEP, p.Arg337Leu was non-functional with loss-of-function findings and monomerization, supporting a damaging effect on protein function and meeting PS3.

4

In the TP53-specific computational framework, SpliceAI predicts no splice effect (max delta score 0.00) and the TP53 VCEP bioinformatic worksheet assigns BP4 with a BayesDel score of 0.0670081; REVEL was 0.765, but the TP53 precomputed PP3/BP4 assignment supports BP4 rather than PP3 for this variant.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 5, 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 substitution, not a nonsense, frameshift, canonical splice, or other null variant. Available evidence does not support a loss-of-function null mechanism for PVS1 application under the TP53-specific framework.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified by the TP53 VCEP at a qualifying pathogenic or likely pathogenic level.	cspec clinvar
PS2	Not assessed	No confirmed de novo observations with the point-based TP53 evidence required for PS2 were identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	In the TP53 VCEP functional worksheet, p.Arg337Leu is summarized as non-functional with loss-of-function findings across eligible assays and monomerization, which supports a damaging effect on TP53 protein function. This meets TP53 PS3 at strong strength.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:16007150 PMID:30224644
PS4	Not assessed	Although this variant is rare in population databases, no case-level TP53 point total from affected individuals was identified to support PS4 under the Li-Fraumeni syndrome scoring framework.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PM1	Not met	This missense variant is not in one of the TP53 codons pre-specified for PM1, and the available hotspot review did not verify that this exact amino acid change is listed in Cancer Hotspots with the somatic recurrence required for TP53 PM1 application.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003 (0.003%) in a large sequenced population.	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, and this variant is not a protein length-changing in-frame indel or stop-loss event.	cspec
PM5	Not assessed	No qualifying same-residue pathogenic or likely pathogenic comparator variant was confirmed from the available reviewed materials, so PM5 was not applied.	cspec pm5_candidates clinvar
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to show cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses.	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 met	The TP53 VCEP bioinformatic worksheet assigns BP4 rather than PP3 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of at least 0.16, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.765, but the TP53-specific precomputed PP3/BP4 assignment does not support PP3 for this variant.	cspec vcep_pp3_bp4_codes bayesdel spliceai revel vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	No blood variant allele fraction or mosaicism-related clinical observations were identified to support TP53 PP4.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the TP53 BA1 threshold of at least 0.001 (0.1%) in a qualifying population.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 threshold of at least 0.0003 in a qualifying population.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in the number of unrelated females age 60 years or older without cancer required for TP53 BS2.	cspec
BS3	Not met	Available TP53 functional evidence does not show retained function. Instead, the TP53 VCEP functional worksheet summarizes p.Arg337Leu as non-functional with loss-of-function findings, which argues against BS3.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:16007150 PMID:30224644
BS4	Not assessed	No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers.	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	Met	The TP53 VCEP bioinformatic worksheet assigns BP4 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the no-splicing-impact threshold of 0.2. These findings support BP4.	cspec vcep_pp3_bp4_codes bayesdel spliceai revel 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 is intended for synonymous or certain intronic variants, whereas this is a missense substitution.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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