Variant classification summary

NM_000141.4:c.346G>A

FGFR2 · NP_000132.3:p.(Glu116Lys) · NM_000141.4

GRCh37: chr10:123324982 C>T · GRCh38: chr10:121565468 C>T

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Glu116Lys)

gnomAD AF

1.2390084463205785e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): allele frequency 1.24e-06 (2/1,614,194 alleles) is far below the 0.1% threshold, and the variant is absent from gnomAD v2.1.

2

BP4 (Supporting): REVEL 0.26, BayesDel -0.24425, and SpliceAI max delta 0.09 all predict no impact on the gene product.

3

VUS: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) conflict and satisfy no ACMG/AMP 2015 combination rule.

Final determination: Generic ACMG/AMP 2015 fallback combination rules (PMID:25741868): with only PM2 (supporting) and BP4 (supporting) applied - 1 supporting pathogenic plus 1 supporting benign - no benign, likely benign, likely pathogenic, or pathogenic combination threshold is met, and the conflicting evidence leaves the variant as Variant of Uncertain Significance.

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.346G>A is a missense change (p.Glu116Lys), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing p.Glu116Lys is documented in ClinVar or the literature.	clinvar pm5_candidates generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband genotype, parental testing, or de novo evidence is available for this variant.
PS3	Not assessed	Not assessed: no well-established functional study of p.Glu116Lys was available.	oncokb spliceai revel bayesdel clinvar
PS4	Not assessed	Not assessed: no case-control or affected-cohort data exist; the only occurrence is 3 somatic cancer entries in COSMIC.	clinvar gnomad_v4 gnomad_v2
PM1	Not met	Not met: p.Glu116 is not a statistically significant mutation hotspot, and no source places it in a critical functional domain.	oncokb gnomad_v4 generic_acmg_combination_rules
PM2	Met	Met (supporting): allele frequency 1.24e-06 (2/1,614,194 alleles, 0.00012%) is far below the 0.1% threshold, and the variant is absent from gnomAD v2.1.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: FGFR2 germline disease is autosomal dominant, so the recessive in-trans requirement of PM3 does not apply.	generic_acmg_combination_rules
PM4	N/A	Not applicable: as a missense change, c.346G>A does not alter protein length, so PM4 does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense at p.Glu116 (e.g., p.Glu116Val) is documented in ClinVar or the literature.	pm5_candidates clinvar generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of c.346G>A is documented in any proband.
PP1	Not assessed	Not assessed: no family or pedigree data exist to evaluate co-segregation of c.346G>A with disease.
PP2	Not assessed	Not assessed: FGFR2 missense variants are a known disease mechanism, but missense constraint metrics needed for the second prong are unavailable.	pvs1_gene_context oncokb generic_acmg_combination_rules
PP3	Not met	Not met: all computational lines are neutral - SpliceAI max delta 0.09 vs 0.2, REVEL 0.26 vs 0.644, BayesDel -0.24425 - so no deleterious effect is predicted.	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history is available to evaluate phenotype specificity.	pvs1_gene_context
PP5	N/A	Not applicable: ClinVar has no expert-panel classification for c.346G>A; the variant is absent from ClinVar.	clinvar
BA1	Not met	Not met: highest observed allele frequency is 1.69e-06 (0.00017%), roughly 4 orders of magnitude below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: observed allele frequency 1.24e-06 (0.00012%) is over 3 orders of magnitude below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: only 2 heterozygous carriers (0 homozygotes) among 1,614,194 alleles, far short of the multiple healthy-adult observations BS2 requires.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional study showing absence of a damaging effect is available; in silico predictions do not qualify.	oncokb spliceai revel bayesdel clinvar
BS4	Not assessed	Not assessed: no family data exist to evaluate non-segregation of the variant.
BP1	Not met	Not met: FGFR2 disease is caused by activating missense variants, not truncating variants, so BP1's premise does not apply.	pvs1_gene_context oncokb generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no proband observation with phase information relative to a pathogenic FGFR2 variant is available.	generic_acmg_combination_rules
BP3	N/A	Not applicable: c.346G>A is a missense change, not an in-frame indel in a repetitive region, so BP3 does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.26 (benign-supporting band 0.183-0.290), BayesDel -0.24425, and SpliceAI max delta 0.09 (below 0.2) all predict no impact.	revel bayesdel spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband molecular workup exists to establish an alternate molecular basis for disease.	clinvar
BP6	N/A	Not applicable: ClinVar has no expert-panel benign classification for c.346G>A; the variant is absent from ClinVar.	clinvar
BP7	N/A	Not applicable: c.346G>A is a missense change, not a synonymous variant, so BP7 does not apply.	generic_acmg_combination_rules

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