Variant classification summary

NM_006218.4:c.1930T>C

PIK3CA · NP_006209.2:p.(Tyr644His) · NM_006218.4

GRCh37: chr3:178937755 T>C · GRCh38: chr3:179219967 T>C

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Tyr644His)

gnomAD AF

6.220816594152681e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1930T>C (p.Tyr644His) variant has not been reported in ClinVar, and Cancer Hotspots did not identify a statistically significant hotspot at Tyr644 in the reviewed record.

2

This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,607,506 alleles; AF 6.22082e-07; 0 homozygotes), which satisfies PM2_Supporting under the Brain Malformations VCEP and is far below the BA1 and BS1 population thresholds.

3

Tyr644 lies outside the PIK3CA Table 4 PM1 domains (amino acids 322-483 and 797-1068), so domain-based PM1 support was not established.

4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.02); REVEL 0.613 and BayesDel 0.183264 were available, but PP3 and BP4 are not applicable to this missense variant under the Brain Malformations VCEP.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 1, 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	The Brain Malformations VCEP considers PVS1 not applicable for PIK3CA because the disease mechanism is gain of function rather than loss of function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS1	Not assessed	No previously established pathogenic variant causing the same amino acid change was identified in the available records, so PS1 could not be confirmed.	clinvar pm5_candidates
PS2	Not assessed	No confirmed de novo data, parental testing results, or tissue-specific allele fraction data were identified for this variant, so PS2 could not be applied.	cspec
PS3	Not assessed	No validated variant-specific functional study meeting the Brain Malformations VCEP requirements was identified, so PS3 was not applied.	cspec oncokb
PS4	Not met	Although PM2 is satisfied, no affected-case point evidence meeting the Brain Malformations VCEP PS4 scoring framework was identified for this variant, so PS4 is not met.	cspec clinvar
PM1	Not met	The Brain Malformations VCEP allows PM1 only as Supporting for variants within approved PIK3CA Table 4 domains (amino acids 322-483 or 797-1068). Tyr644 lies outside these intervals, and Cancer Hotspots did not identify a statistically significant hotspot at this residue.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,607,506 alleles; AF 6.22082e-07; 0 homozygotes), which is within the Brain Malformations VCEP allowance of one person maximum for PM2_Supporting.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
PM5	Not assessed	No established pathogenic missense comparator at the same residue was confirmed from the available records, so PM5 could not be applied.	pm5_candidates clinvar
PM6	N/A	PM6 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
PP2	Not assessed	The Brain Malformations VCEP allows PP2 for PIK3CA only when the missense constraint z-score is greater than 3.09, but that gene-level value was not available in the reviewed evidence, so PP2 was not assessed.	cspec
PP3	N/A	PP3 is not applicable under the Brain Malformations VCEP for this variant type. Computational scores were available, including REVEL 0.613, BayesDel 0.183264, and SpliceAI max delta score 0.02, but they are not used to apply PP3 in this PIK3CA framework.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
PP5	N/A	PP5 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
BA1	Not met	The highest observed population frequency is 6.22082e-07 in gnomAD v4.1 (0.00006%), which is far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The highest observed population frequency is 6.22082e-07 in gnomAD v4.1 (0.00006%), which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.	gnomad_v4 cspec
BS2	Not met	This variant has 0 homozygotes in gnomAD and no well-phenotyped unaffected family observations were identified, so the Brain Malformations VCEP BS2 requirement of at least 3 qualifying observations is not met.	gnomad_v4 cspec
BS3	Not assessed	No well-established benign functional study showing normal effect for this variant was identified, so BS3 was not applied.	cspec oncokb
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP because these disorders are typically de novo, germline mosaic, or post-zygotic.	cspec
BP1	N/A	BP1 is not applicable for PIK3CA in this VCEP because the disease mechanism is gain of function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.	cspec
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
BP4	N/A	BP4 is limited by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants with no predicted splice impact, so it is not applicable to this missense variant. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but that does not make BP4 applicable here.	cspec spliceai
BP5	Not assessed	No evidence was identified showing an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not applied.	cspec
BP6	N/A	BP6 is not applicable under the Brain Malformations VCEP for this disease framework.	cspec
BP7	N/A	BP7 is restricted by the Brain Malformations VCEP to synonymous, intronic, or non-coding variants and is not applicable to this missense variant.	cspec

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