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
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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 · 18 PMIDs triaged · 8 high-priority
18papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
22046346 ↗
functional
Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib.
Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact
BS3PM1PS3
30531871 ↗
functional
Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.
Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER+ breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25-30% of people treated with aromatase inhibitors1-4, knowledge about clinical resistance mechani
BS3PM1PS3
18413839 ↗
functional
EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation.
Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib. We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were de
BS3PM1PS3
22046346 ↗
splicing rna
Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib.
Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact
BP7PP3PP5PS4PVS1
23220880 ↗
functional
Activating HER2 mutations in HER2 gene amplification negative breast cancer.
Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, includi
BS3PM1PS3
26619011 ↗
functional
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorit
BS3PM1PS3
29420467 ↗
functional
HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological
BS3PM1PS3
30314968 ↗
functional
Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.
We examined the role of ERBB2-activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HER
BS3PM1PS3
23619274 ↗
background review
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
PP5PS4
Sources & reference links