Variant classification summary

NM_000546.6:c.1066G>C

TP53 · NP_000537.3:p.(Gly356Arg) · NM_000546.6

GRCh37: chr17:7573961 C>G · GRCh38: chr17:7670643 C>G

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM2 supporting BS3 strong BP4 moderate BP6 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gly356Arg)

gnomAD AF

4.337163668447382e-06 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): total allele frequency 4.34e-06, below the VCEP <0.00003 threshold.

2

BS3 (Strong): Kato et al. classify p.(Gly356Arg) as fully functional with no loss of function.

3

BP4 (Moderate): BayesDel -0.347 meets the <=-0.008 cutoff; SpliceAI predicts no splicing impact (max delta 0.004).

4

BP6 (Supporting): ClinGen TP53 Variant Curation Expert Panel classified this exact variant as Likely Benign.

5

Overall Likely Benign: PM2 (+1) + BS3 (-4) + BP4 (-1) + BP6 (-1) = -5, within Rule4 (-6 to -2).

Final determination: TP53 VCEP v2.4 Rule4: point sum in [-6,-2] -> Likely Benign; sum here = -5.

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.1066G>C is a missense substitution, not a null variant (nonsense, frameshift, or splice-site change).	cspec vcep_pvs1_flowchart
PS1	Not assessed	Not assessed: no other nucleotide change producing the identical p.(Gly356Arg) protein with a Pathogenic classification was identified.
PS2	Not assessed	Not assessed: no de novo occurrence or documented parental testing for this variant is available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: Kato et al. transactivation data classify p.(Gly356Arg) as fully functional, the opposite of the loss-of-function pattern PS3 requires.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec
PS4	Not assessed	Not assessed: no qualifying germline proband with this exact variant, phenotype, or cancer-point evidence is documented.	cspec vcep_ps4_points_table PMID:17392385 PMID:21519010 PMID:22186996 PMID:24356096 PMID:24493721 PMID:25394175
PM1	Not met	Not met: codon 356 is not among the VCEP hotspot codons (175, 245, 248, 249, 273, 282) and shows no significant cancerhotspots occurrence.	cspec
PM2	Met	Met (Supporting): total allele frequency 4.34e-06 is below the VCEP threshold of <0.00003 in gnomAD v4.1.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly designates PM3 as not applicable for this gene.	cspec
PM4	N/A	Not applicable: this missense substitution does not alter protein length, and the TP53 VCEP marks PM4 as not applicable.	cspec
PM5	Not assessed	Not assessed: no pathogenic variant at codon 356 was identified; known G356A and G356E changes carry benign-leaning classifications.
PM6	N/A	Not applicable: the TP53 VCEP specifies PM6 as not applicable for this variant.	cspec
PP1	Not assessed	Not assessed: no affected relatives with confirmed testing are documented, so cosegregation cannot be established.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP marks PP2 as not applicable for missense variants.	cspec
PP3	Not met	Not met: BayesDel score -0.347 is far below the >=0.16 threshold, and SpliceAI predicts no splicing impact (max delta 0.004).	cspec bayesdel spliceai
PP4	Not assessed	Not assessed: no qualifying low-VAF multigene-panel observation of this variant is available.	cspec
PP5	Not met	Not met: the expert-panel ClinVar assertion for this exact variant is Likely Benign, not Pathogenic or Likely Pathogenic.	clinvar
BA1	Not met	Not met: maximum continental-subpopulation allele frequency 5.93e-06 is far below the 0.001 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: maximum continental-subpopulation allele frequency 5.93e-06 is below the 0.0003 BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented count of unrelated women reaching age 60 without cancer is available.
BS3	Met	Met (Strong): Kato et al. transactivation data classify p.(Gly356Arg) as fully functional with no loss of function, per the TP53 VCEP worksheet.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes cspec
BS4	Not assessed	Not assessed: no affected family members with documented absence of the variant are identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP marks BP1 as not applicable for missense variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP designates BP2 as not applicable for this variant.	cspec
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame indel in a repeat region.	cspec
BP4	Met	Met (Moderate): BayesDel -0.347 meets the <=-0.008 cutoff, and SpliceAI predicts no splicing impact (max delta 0.004). Flagged for human review: the aGVGD C65 exclusion could not be confirmed.	cspec bayesdel spliceai
BP5	N/A	Not applicable: the TP53 VCEP designates BP5 as not applicable.	cspec
BP6	Met	Met (Supporting): the ClinGen TP53 Variant Curation Expert Panel classified this exact variant as Likely Benign.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; c.1066G>C is a missense substitution.	cspec

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