Variant classification summary

NM_004448.4:c.929C>T

ERBB2 · NP_004439.2:p.(Ser310Phe) · NM_004448.4

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

Gene: ERBB2 Transcript: NM_004448.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Ser310Phe)

gnomAD AF

ClinVar

Oncogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: S310F/S310Y increased oncogenic cellular phenotypes and ERBB2 pathway activity versus wild-type in two cell models.

2

PM1 moderate: ERBB2 S310 is identified as a statistically significant mutational hotspot.

3

PM2 supporting: the variant is absent from the available gnomAD datasets.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 moderate plus 2 supporting criteria satisfies no pathogenic, likely pathogenic, benign, or likely benign rule, so 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 assessed	Not assessed: no previously established pathogenic variant with the same Ser310Phe amino-acid change through a different nucleotide change was identified.	PMID:29954840
PS2	Not assessed	Not assessed: No proband phenotype, confirmed maternity and paternity, parental genotypes, or family-history data establish a confirmed germline de novo event.
PS3	Met	Met at supporting strength: S310F/S310Y increased proliferation, colony formation, migration, signaling, and PD-L1 versus wild-type ERBB2 in two cell models.	PMID:29954840
PS4	Not assessed	Not assessed: no affected-case and control counts, odds ratio, or confidence interval were available to test the PS4 requirement of OR >5.0 with a confidence interval excluding 1.0.	PMID:22918138
PM1	Met	Met: ERBB2 S310 is identified as a statistically significant hotspot, and the index variant is absent from both gnomAD v2.1 and v4.1.	hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, corresponding to an observed frequency of 0 below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, pathogenic-partner, or parental/offspring phase data establish a pathogenic variant 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 assessed	Not assessed: ERBB2 S310Y was functionally studied, but it was not established as pathogenic under the required PM5 condition.	PMID:29954840
PM6	Not assessed	Not assessed: No affected germline proband or parental testing supports an assumed de novo occurrence without maternity and paternity confirmation.
PP1	Not assessed	Not assessed: No affected relatives, family genotypes, phenotype assessments, or informative meioses document co-segregation with disease.
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and a common missense disease mechanism for ERBB2.
PP3	Not met	Not met: missense REVEL 0.533 is below the supporting PP3 threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history was supplied that is highly specific for a disease with a single genetic etiology.
PP5	Not met	Not met: ClinVar shows one somatic single-submitter Oncogenic record, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar PMID:22918138
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, giving an observed allele frequency of 0 versus the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: observed allele frequency was 0 in gnomAD v2.1 and v4.1, below the generic BS1 threshold of 1% and not greater than expected.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy adult carrier was identified, and the variant was absent from gnomAD v2.1, v4.1, and the reported non-cancer subsets.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay demonstrates that ERBB2 S310F has no damaging effect on protein function or splicing.
BS4	Not assessed	Not assessed: No tested affected relatives, family genotypes, phenotype data, or informative meioses demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not show that ERBB2 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic partner allele or cis/trans phase result establishes the BP2 configuration in an affected proband.
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 0.533 is above the supporting BP4 threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case was documented with this variant plus an alternate molecular basis for the disease.	PMID:29954840
BP6	Not met	Not met: no exact-variant expert-panel Benign or Likely benign classification was found; ClinVar instead reports a single-submitter somatic Oncogenic record.	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.