NM_004448.4:c.929C>A

ERBB2 · NP_004439.2:p.(Ser310Tyr) · NM_004448.4

GRCh37: chr17:37868208 C>A · GRCh38: chr17:39711955 C>A

Gene: ERBB2 Transcript: NM_004448.4

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Ser310Tyr)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PS3 strong: ERBB2 S310Y showed concordant gain-of-function effects across independent cell-based assays.

PM2 supporting: the variant is absent from evaluated gnomAD datasets and meets the generic supporting threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus one supporting pathogenic criterion does not meet a listed pathogenic or likely pathogenic combination, and no benign rule is satisfied; therefore the call is VUS.

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: no distinct nucleotide substitution producing the same p.Ser310Tyr change is established as pathogenic in the reviewed evidence.	clinvar PMID:22908275 PMID:24997986 PMID:29420467 PMID:29967253
PS2	Not assessed	Not assessed: no documented affected proband, family-history information, or confirmed maternity and paternity establishes a de novo event.
PS3	Met	Met, strong: ERBB2 S310Y produced robust transformation and increased proliferation across independent cell-based assays with wild-type, mock, and pathway-relevant controls.	PMID:22908275 PMID:24997986
PS4	Not assessed	Not assessed: reviewed studies lack eligible germline case-control counts or a matched control frequency needed to calculate the PS4 odds ratio and 95% confidence interval.	PMID:22908275 PMID:24997986 PMID:29420467 PMID:29967253
PM1	Not assessed	Not assessed: S310 is reported as a hotspot, but absence of benign variation across the relevant region is not established.	hotspots PMID:22908275 PMID:29420467
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PM2 allele-frequency threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no pathogenic second allele or parental/offspring testing establishes that ERBB2 p.Ser310Tyr is in trans.
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 met	Not met: S310F is reported as oncogenic, but no different S310 missense variant is established as pathogenic in the reviewed evidence.	PMID:22908275 PMID:29420467 PMID:29967253
PM6	Not assessed	Not assessed: no affected proband or parental testing supports an assumed de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or phenotype-consistent segregation data are reported for this variant.
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and a common disease-causing missense mechanism for ERBB2.
PP3	Not met	Not met: missense REVEL 0.54 is below the PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar has one exact-variant Pathogenic single-laboratory submission, but no qualifying expert-panel classification for PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the BA1 filtering-allele-frequency threshold of 0.05.	gnomad_v2 gnomad_v4 clinvar
BS1	Not met	Not met: no gnomAD filtering allele frequency or grpmax FAF was observed, so the variant is not above the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult observation or homozygote, heterozygote, or hemizygote count is documented for this variant.	clinvar gnomad_v2 gnomad_v4
BS3	Not met	Not met: S310Y increased transformation, IL-3-independent growth, and cell proliferation in direct assays rather than showing no damaging effect.	PMID:22908275 PMID:24997986
BS4	Not assessed	Not assessed: no affected relatives with genotype and phenotype data are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the reviewed evidence does not establish that ERBB2 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic partner allele and no phase result establish cis or trans for ERBB2 p.Ser310Tyr.
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 0.54 is above the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: somatic cancer reports do not document a patient with an alternate molecular basis for the relevant disease.	PMID:22908275 PMID:24997986 PMID:29420467
BP6	Not met	Not met: no qualifying expert-panel Benign or Likely benign classification exists for this exact variant in ClinVar.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.