NM_004448.4:c.2264T>C (p.Leu755Ser) in ERBB2 is a missense variant located in the protein kinase domain at a statistically significant mutational hotspot. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_moderate).1 The variant lies in the kinase domain (aa 720–987), a critical functional region with no benign variation observed at this residue, meeting PM1 at the moderate level.2 Multiple well-established in vitro functional studies demonstrate p.Leu755Ser is an activating (gain-of-function) mutation that hyperactivates downstream RAS/MAPK and PI3K/AKT signaling and confers resistance to endocrine and HER2-targeted therapies (PS3_moderate).3 In silico meta-predictor REVEL yields a score of 0.86, supporting a deleterious effect (PP3_supporting).4 No de novo occurrence, co-segregation data, or germline case-control studies have been reported for this variant. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile of 3 moderate criteria (PS3, PM1, PM2) and 1 supporting criterion (PP3) meets the Likely Pathogenic classification threshold (≥3 moderate criteria).5
ERBB2
Final classification
Likely Pathogenic
ERBB2 c.2264T>C · p.Leu755Ser
ERBB2
NM_004448.4:c.2264T>C (p.Leu755Ser) in ERBB2 is a missense variant located in the protein kinase domain at a statistically significant mutational hotspot.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PP3
Likely Pathogenic
ERBB2 c.2264T>C
PS3 + PM1 + PM2 + PP3
→
Likely Pathogenic
Gene diagram
· NM_004448.4 · variants mapped to exon structure
ERBB2
NM_004448.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 376035)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.86. BayesDel score = 0.312741.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54062780, n = 173 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2(+) Breast Cancer.
Found
(Xu et al.
Applied to
→PS3 supports · met
Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.
Searched
c.2264T>Cp.Leu755SerL755S
Found
L755S conferred resistance to estrogen deprivation, tamoxifen, fulvestrant, and GDC-0810 in T47D and MCF7 ER+ breast cancer cells, with hyperphosphorylation of ERK and AKT, suppression of ER signaling (downregulated ESR1, PGR, GREB1), and induction of a RAS/MAPK transcriptional signature. Neratinib restored fulvestrant sensitivity.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data confirmed gain-of-function effect with endocrine and HER2-targeted therapy resistance; referenced in PS3 (moderate) and BS3 (not met, contradictory) assessments.
The kinase domain mutants HER2 p.Leu755Ser, p.Val777Leu, and p.Leu869Arg have previously been identified and characterized as activating in breast cancer
Location Results para 1 (patient cohort); Figure 3a–g (functional assays); Figure 6a–d (neratinib rescue) · Context T47D and MCF7 ER+ breast cancer cell lines; lentiviral transduction; CellTiter-Glo viability assay; western blot for p-ERK/p-AKT; qRT-PCR for ER target genes; RNA-seq transcriptomic profiling · full text
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
18413839 ↗
EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation.
ONCOKB
26619011 ↗
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
ONCOKB
30314968 ↗
Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.
ONCOKB
23619274 ↗
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
CLINVAR