Variant classification summary

NM_002067.5:c.626A>C

GNA11 · NP_002058.2:p.(Gln209Pro) · NM_002067.5

GRCh37: chr19:3118942 A>C · GRCh38: chr19:3118944 A>C

Gene: GNA11 Transcript: NM_002067.5

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PM5 moderate PP3 moderate

Variant details

Gene

GNA11

Transcript

NM_002067.5

Protein

NP_002058.2:p.(Gln209Pro)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PM1 moderate supports the codon-209 hotspot mechanism.

2

Likely Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

3

Likely Pathogenic: PM5 moderate is supported by tumorigenic GNA11 p.Gln209Leu at the same residue.

4

Likely Pathogenic: PP3 moderate is supported by REVEL 0.869.

Final determination: Under the generic ACMG/AMP 2015 fallback, three moderate pathogenic criteria (PM1, PM5, and PP3) support Likely Pathogenic; PM2 supporting is additional evidence.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: GNA11 p.Gln209Pro was reported in tumor sequencing, but no prior established pathogenic record for the same amino-acid change is demonstrated.	PMID:21083380 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history assessment, or parental testing confirming both maternity and paternity is available.
PS3	Not assessed	Not assessed: Q209P was reported at 2.7% of codon-209 mutations, but no variant-specific functional assay established a damaging effect.	PMID:21083380 PMID:29490280 PMID:26825879
PS4	Not assessed	Not assessed: Q209P was 2.7% of codon-209 GNA11 mutations, but no affected-versus-control counts or OR/RR with a confidence interval were reported.	PMID:21083380 PMID:26825879 PMID:29490280
PM1	Met	Met: p.Gln209Pro lies at the statistically significant GNA11 codon-209 cancer hotspot and is absent from both gnomAD v2.1 and v4.1.	hotspots PMID:21083380 PMID:29490280 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, second pathogenic allele, parent testing, or phase result shows GNA11 p.Gln209Pro in trans.	clinvar PMID:21083380
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	Met: the same GNA11 residue has the functionally tumorigenic p.Gln209Leu substitution, with constitutive signaling and melanocytic tumor formation reported in models.	PMID:26825879 PMID:29490280
PM6	Not assessed	Not assessed: no documented de novo occurrence or parental testing supports assuming this variant arose de novo.
PP1	Not assessed	Not assessed: no affected relatives, pedigree, segregation testing, or meioses are documented for evaluating co-segregation.
PP2	Not assessed	Not assessed: no validated gene-level evidence establishes both a low benign-missense rate and a common missense disease mechanism for GNA11.
PP3	Met	Met at moderate: missense REVEL score 0.869 meets the >=0.773 PP3 moderate threshold.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history highly specific for a single-genetic-etiology disease was documented.
PP5	Not met	Not met: ClinVar is Pathogenic but has zero expert-panel submissions and only a single-submitter laboratory classification.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no grpmax FAF reaches the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF at or above the generic >=0.01 BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult, homozygous, heterozygous, or hemizygous observation with age and phenotype data is available.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific assay demonstrated that GNA11 p.Gln209Pro has no damaging effect on protein function or splicing.	PMID:21083380 PMID:29490280 PMID:26825879
BS4	Not assessed	Not assessed: no affected family members with documented genotypes and phenotypes are available to evaluate lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not establish that GNA11 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no parent or family testing demonstrates p.Gln209Pro in trans with a pathogenic variant or in cis with any pathogenic variant.	clinvar PMID:21083380
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.869 exceeds the <=0.29 BP4 supporting threshold.	revel
BP5	Not assessed	Not assessed: no qualifying case was documented in which this exact variant co-occurred with an alternate molecular basis for disease.
BP6	Not met	Not met: the exact-variant ClinVar record is Pathogenic from a single submitter, with no expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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