Variant classification summary

NM_001982.4:c.310G>A

ERBB3 · NP_001973.2:p.(Val104Met) · NM_001982.4

GRCh37: chr12:56478854 G>A · GRCh38: chr12:56085070 G>A

Gene: ERBB3 Transcript: NM_001982.4

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting

Variant details

Gene

ERBB3

Transcript

NM_001982.4

Protein

NP_001973.2:p.(Val104Met)

gnomAD AF

6.195418364211298e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong functional studies show ERBB2-dependent survival, signaling, transformation, and in vivo growth.

2

Likely Pathogenic: PM1 moderate places Val104 in a statistically significant Cancer Hotspots mutational hotspot.

3

Likely Pathogenic: PM2 supporting reflects the gnomAD v4.1 allele frequency of 6.19542e-07 with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong plus one moderate plus one supporting pathogenic criterion supports Likely Pathogenic.

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 assessed	Not assessed: no independent pathogenic observation of the same Val104Met amino-acid change caused by a different nucleotide change was established.	clinvar PMID:29533785
PS2	Not assessed	Not assessed: no proband phenotype, family-history information, or confirmed maternity and paternity are documented for this variant.
PS3	Met	Met, strong: p.Val104Met produced approximately 10- to 300-fold interleukin-3-independent BaF3 survival with ERBB2 and promoted concordant signaling, transformation, and in vivo growth.	PMID:23680147 PMID:29533785
PS4	Not assessed	Not assessed: no germline affected-versus-control counts, odds ratio, or confidence interval are available for this variant.	PMID:22918138 PMID:34131312 PMID:29533785 cosmic gnomad_v4
PM1	Met	Met, moderate: Cancer Hotspots identifies residue V104 as a statistically significant hotspot, while gnomAD v4.1 shows AF 6.19542e-07.	hotspots gnomad_v4
PM2	Met	Met at supporting: gnomAD v4.1 AF 6.19542e-07 (1/1,614,096 alleles, zero homozygotes) is below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring testing establishes this variant in trans with a pathogenic allele.
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	Not assessed	Not assessed: no different missense substitution at ERBB3 Val104 was established as pathogenic in the available evidence.	pm5_candidates clinvar PMID:29533785
PM6	Not assessed	Not assessed: no affected proband and no parental testing establishing an assumed de novo occurrence are documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or variant-positive family members with concordant disease are documented.
PP2	Not assessed	Not assessed: no validated ERBB3 benign-missense rate and common-missense disease mechanism were established together.
PP3	Not met	Not met: REVEL 0.584 is below the >=0.644 generic supporting PP3 threshold for missense variants.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to establish a highly specific ERBB3-associated disease presentation.
PP5	Not met	Not met: ClinVar has zero exact-variant expert-panel submissions, despite a non-expert somatic Pathogenic record.	clinvar PMID:29533785
BA1	Not met	Not met: gnomAD v4.1 AF 6.19542e-07 is far below the >=0.05 BA1 threshold, with zero homozygotes observed.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 AF 6.19542e-07 is far below the generic >=0.01 BS1 threshold, so no elevated-frequency signal exists.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but no qualifying healthy-adult observation or early-onset full-penetrance disease model is documented.	gnomad_v4
BS3	Not met	Not met: p.Val104Met increased ERBB2-dependent signaling, transformation, survival, and in vivo growth rather than showing preserved function.	PMID:23680147
BS4	Not assessed	Not assessed: no tested affected relatives with documented absence of the variant are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: ERBB3 loss-of-function disease is reported, but a primarily truncating disease spectrum was not established.
BP2	Not assessed	Not assessed: no documented pathogenic variant in trans or cis, and no phase or inheritance data are available.
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: REVEL 0.584 is above the <=0.29 generic supporting BP4 threshold for missense variants.	revel
BP5	Not assessed	Not assessed: no case documents this exact variant alongside an alternate molecular explanation for the patient's disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is present.	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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