Variant classification summary

NM_000546.6:c.1010G>A

TP53 · NP_000537.3:p.(Arg337His) · NM_000546.6

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

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Arg337His)

gnomAD AF

3.098166009648928e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS2 is not assessed because no qualifying de novo proband with parental-testing evidence and an eligible cancer was documented.

2

PM6 is not applicable under the TP53 VCEP CSPEC.

3

PP1 is not assessed because the reviewed family reports do not provide an auditable informative meiosis count.

4

BS4 is not assessed because affected-family-member non-segregation was not demonstrated under the VCEP definition.

5

The VCEP-governed output is limited to PS4, PP4, PP5, BP5, and BP6. PP5, BP5, and BP6 are not applicable under the TP53 VCEP specification. PP4 lacks the required low-VAF multigene-panel observations. PS4 has exact-variant case-control evidence, but the reported counts do not provide the VCEP PS4 point categories needed for a strength assignment; the corrected OR is 13.09 with 95% CI 0.67-255.59, which includes 1.

6

The governing framework is the ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4.

7

The exact PP3-BP4 lookup row for c.1010G>A / p.Arg337His assigns Class C0, BayesDel 0.177746, and No evidence; that pre-assignment governs PP3 and BP4.

8

SpliceAI reports a maximum delta score of 0.001, below the VCEP 0.2 splice-impact threshold, but this does not overcome the missense BayesDel requirement for BP4.

9

BP7 is not applicable because the variant is missense rather than synonymous or intronic.

Final determination: Under the ClinGen TP53 Version 2.4 point-based framework, a total score of 0 falls within the -1 to 5 range assigned to VUS.

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.1010G>A is a missense variant, whereas the VCEP PVS1 rule governs null-variant pathways and neither PVS1 table lists this variant.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: SpliceAI is 0.001, but no distinct pathogenic or likely pathogenic nucleotide change producing the same p.Arg337His substitution was identified.	cspec pm5_candidates spliceai
PS2	Not assessed	Not assessed: no qualifying de novo proband and parental-testing evidence were reported for R337H, so the VCEP's 1-point minimum for PS2_Supporting cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:16033918
PS3	Not met	Not met: the VCEP worksheet assigns R337H the pre-assigned functional code No evidence, with Kato partially functional and Giacomelli noLOF.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not assessed	Not assessed: R337H had corrected OR 13.09, but its 95% CI was 0.67-255.59 and available data lacked the VCEP-required proband point categories.	cspec vcep_ps4_points_table PMID:10864200 PMID:16033918 PMID:16494995 PMID:19046423
PM1	Not met	Not met: p.Arg337His is codon 337, outside the six specified codons, and has 4 cancerhotspots observations versus the required threshold of at least 10.	cspec clinvar
PM2	Not met	Not met: Admixed American gnomAD v4.1 AF is 0.0000500283 from 3 alleles, exceeding the VCEP PM2 multi-allele limit of 0.00004.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly excludes PM3 for TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the ClinGen TP53 VCEP specification explicitly marks PM4 as Not Applicable.	cspec
PM5	Not assessed	Not assessed: R337C and R337G have functional results, but neither is established as pathogenic or likely pathogenic under the TP53 VCEP without PM5.	cspec pm5_candidates vcep_functional_worksheet
PM6	N/A	Not applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable for this framework.	cspec
PP1	Not assessed	Not assessed: R337H was reported in multiple families, but no informative meiosis count was available to reach the VCEP's minimum 3-4 meioses for PP1_Supporting.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:10864200 PMID:16033918 PMID:16494995
PP2	N/A	Not applicable: The TP53 VCEP explicitly designates PP2 as not applicable.	cspec
PP3	Not met	Not met: VCEP Table S2 pre-assigns No evidence with BayesDel 0.177746, and SpliceAI max delta 0.001 is below the PP3 threshold of 0.2.	cspec vcep_pp3_bp4_codes spliceai
PP4	Not assessed	Not assessed: no qualifying multigene-panel VAF observations were available for the VCEP PP4 thresholds of 5-25% or 5-35%.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly prohibits PP5 use, regardless of available pathogenic reports.	cspec
BA1	Not met	Not met: gnomAD v4.1 maximum joint FAF is 0.00001328, below the TP53 VCEP BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum joint FAF is 0.00001328, below the TP53 VCEP BS1 lower threshold of 0.0003.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying count of unrelated female carriers cancer-free to age 60 from a single source is available.	cspec
BS3	Not met	Not met: the VCEP worksheet assigns R337H No evidence rather than BS3, despite Kato partially functional and Giacomelli noLOF assay results.	cspec vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	Not assessed: affected relatives were reported, but the evidence did not document VCEP-defined lack of segregation in affected family members for R337H.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:10864200 PMID:16494995
BP1	N/A	Not applicable: The TP53 VCEP excludes BP1 because truncating variants account for only a portion of disease-causing TP53 variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 as not applicable despite describing trans-phase and phase-unknown observation scenarios.	cspec
BP3	N/A	Not applicable: the ClinGen TP53 VCEP specification explicitly marks BP3 as Not Applicable.	cspec
BP4	Not met	Not met: BayesDel 0.177746 exceeds the VCEP BP4 missense cutoff of <0.16, despite SpliceAI max delta 0.001 indicating no predicted splice impact.	cspec vcep_pp3_bp4_codes spliceai
BP5	N/A	Not applicable: BP5 is explicitly marked not applicable in the TP53 VCEP specification.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly prohibits BP6 use, regardless of available benign reports.	cspec
BP7	N/A	Not applicable: p.(Arg337His) is a missense variant, whereas VCEP BP7 covers synonymous or intronic variants, not protein-changing exonic substitutions.	cspec

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