0%
ERBB2c.2264T>CLikely pathogenic
Print report
Variant interpretation report

ERBB2 c.2264T>C, p.(Leu755Ser)

NM_004448.4:c.2264T>C NP_004439.2:p.(Leu755Ser) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ERBB2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate

Multiple well-established in vitro functional studies demonstrate that p.Leu755Ser is an activating (gain-of-function) mutation in the ERBB2 kinase domain, conferring resistance to endocrine therapies and hyperactivating downstream RAS/MAPK and PI3K/AKT signaling. At least two independent studies (PMID:30531871 and PMID:28487443) confirm the damaging functional effect.

PM1Moderate
PM1 · moderate

The variant is located in the ERBB2 protein kinase domain (aa 720–987), a critical functional region. Residue Leu755 lies in a statistically significant mutational hotspot with recurrent somatic missense alterations (L755S, L755P, L755W) and no benign variation observed at this position.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and v4.1 (allele frequency <0.1%), meeting the PM2 threshold for a rare variant absent from population controls.

PP3Supporting
PP3 · supporting

In silico meta-predictor REVEL gives a score of 0.86, above the 0.5 threshold, supporting a deleterious effect. BayesDel is intermediate (0.313). SpliceAI predicts no splice impact (max delta 0.02), which is neutral for a missense variant. The REVEL score supports PP3 at the supporting level.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
173 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54062780, n = 173 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 18 not met · 2 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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.

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).

In silico meta-predictor REVEL yields a score of 0.86, supporting a deleterious effect (PP3_supporting).

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).

Met · 4

PS3 ModerateMultiple well-established in vitro functional studies demonstrate that p.Leu755Ser is an activating (gain-of-function) mutation in the ERBB2 kinase domain, conferring resistance to endocrine therapies and hyperactivating downstream RAS/MAPK and PI3K/AKT signaling. At least two independent studies (PMID:30531871 and PMID:28487443) confirm the damaging functional effect. Details ▾Hide ▴
Evidence considered
  • PMID:30531871 (Nayar et al. 2019): Full text confirms L755S is an acquired activating HER2 kinase domain mutation. In T47D and MCF7 cells
  • L755S confers strong resistance to estrogen deprivation
  • tamoxifen
  • fulvestrant
  • and GDC-0810
  • hyperphosphorylates ERK and AKT
  • suppresses ER signaling
  • and induces a RAS/MAPK transcriptional signature.
  • PMID:28487443 (Xu et al. 2017): Title specifically identifies L755S as a mechanism of acquired resistance to HER2-targeted therapy in HER2+ breast cancer.
  • OncoKB classifies this alteration as Oncogenic with Gain-of-function effect
  • curated from variant-specific literature.
Still missing
  • Full text not available for PMID:28487443 to extract detailed functional assay data.
  • Additional functional studies (PMID:23220880
  • PMID:29420467
  • PMID:29967253) may provide further support but could not be variant-confirmed from abstracts alone.
Sources
PMID:30531871 ↗oncokb ↗3053187128487443
PM1 ModerateThe variant is located in the ERBB2 protein kinase domain (aa 720–987), a critical functional region. Residue Leu755 lies in a statistically significant mutational hotspot with recurrent somatic missense alterations (L755S, L755P, L755W) and no benign variation observed at this position. Details ▾Hide ▴
Evidence considered
  • Residue 755 is in the kinase domain (aa 720–987)
  • essential for ERBB2 catalytic activity.
  • Statistically significant hotspot per cancerhotspots.org.
  • Recurrent somatic mutations at codon 755 (L755S
  • L755P
  • L755W) in COSMIC.
  • No benign variants reported at this position in ClinVar or gnomAD.
Sources
oncokb ↗
PM2 ModerateThis variant is absent from gnomAD v2.1 and v4.1 (allele frequency <0.1%), meeting the PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Allele frequency effectively 0
  • well below the 0.1% PM2 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingIn silico meta-predictor REVEL gives a score of 0.86, above the 0.5 threshold, supporting a deleterious effect. BayesDel is intermediate (0.313). SpliceAI predicts no splice impact (max delta 0.02), which is neutral for a missense variant. The REVEL score supports PP3 at the supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.86 (damaging).
  • BayesDel score: 0.313 (intermediate
  • non-contributory).
  • SpliceAI max delta: 0.02 (no predicted splice impact).
Still missing
  • Additional in silico predictors (e.g.
  • CADD
  • PolyPhen-2
  • SIFT) were not computed.
Sources
revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS1 No alternative nucleotide change at c.2264 producing the same p.(Leu755Ser) amino acid change has been identified and classified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar variation ID 376035 is the sole entry for this residue change
  • no other nucleotide changes at this position were identified.
Still missing
  • A systematic search for alternative nucleotide changes at codon 755 producing Leu755Ser was not exhaustively performed.
Sources
clinvar ↗
PS2 No de novo germline occurrence of c.2264T>C (p.Leu755Ser) has been reported. Systematic search of de novo databases (Gene4Denovo, denovo-db) returned no record for this variant. All reported observations are somatic. Details ▾Hide ▴
Evidence considered
  • Exploratory agent searched de novo databases
  • no germline de novo events found.
  • Variant is recurrent somatically (COSMIC 173x) but not reported as germline de novo.
Still missing
  • No trio-based sequencing studies for ERBB2 in a germline predisposition context were identified.
PS4 No germline case-control study comparing allele frequency of c.2264T>C in affected individuals versus healthy controls has been performed. The variant is absent from gnomAD, precluding direct case-control comparison. Somatic enrichment (COSMIC 173x) does not satisfy PS4 in a germline classification context. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD v2.1 and v4.1.
  • COSMIC reports 173 somatic occurrences
  • but no germline case-control study has been published.
Still missing
  • A germline case-control study or cohort enrichment analysis would be required to assess PS4.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM5 No pathogenic germline missense variant at the same residue (Leu755) with a different amino acid change was identified. PM5 candidate harvesting found zero same-residue comparator variants with expert panel or majority pathogenic classification in ClinVar. Details ▾Hide ▴
Evidence considered
  • pm5_candidates.json: eligible_for_classic_pm5_search=false
  • total_candidates=0.
  • While somatic L755P and L755W are known
  • no pathogenic germline comparator at this residue was identified.
Still missing
  • L755P and L755W are reported somatically but lack germline pathogenic classification.
Sources
pm5_candidates
PM6 No de novo germline observation of this variant has been reported, with or without confirmed parentage. Same evidence gap as PS2. Details ▾Hide ▴
Evidence considered
  • No de novo germline occurrences identified in databases or literature.
Still missing
  • No de novo observation of this variant exists to evaluate PM6.
PP1 No published co-segregation study for ERBB2 c.2264T>C (p.Leu755Ser) in a germline cancer predisposition family was identified. Targeted literature search yielded only somatic reports. Details ▾Hide ▴
Evidence considered
  • Exploratory agent found no co-segregation or family linkage data for this variant.
Still missing
  • No family-based segregation analysis for germline ERBB2 L755S has been published.
PP2 Insufficient data to establish that ERBB2 has a low rate of benign missense variation in the germline context. No gene-specific missense constraint score (HCI Prior) is available to support PP2; germline ERBB2 disease is primarily associated with loss-of-function variants. Details ▾Hide ▴
Evidence considered
  • HCI Prior not found for ERBB2.
  • Germline ERBB2 disease mechanism is primarily loss-of-function per PVS1 gene context review.
Still missing
  • ERBB2 missense constraint metrics are not available to formally evaluate PP2.
Sources
pvs1_gene_context
PP5 No reputable source has independently classified this variant as pathogenic in a germline context. ClinVar variation ID 376035 has zero submitted classifications. OncoKB labels it as Oncogenic, but this is in a somatic context and does not constitute an independent germline clinical classification. Details ▾Hide ▴
Evidence considered
  • ClinVar: variation ID 376035
  • zero submissions
  • no classification.
  • OncoKB: Oncogenic (somatic context only
  • not a germline clinical classification).
Still missing
  • No expert panel or clinical laboratory has classified this variant in a germline context.
Sources
clinvar ↗oncokb ↗
BA1 This variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). BA1 requires allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: absent.
  • Allele frequency = 0
  • far below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and v4.1. BS1 requires allele frequency >0.3% in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: absent.
  • Allele frequency = 0
  • far below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in a healthy adult individual has been reported for a recessive or fully penetrant disorder. The variant is absent from gnomAD, so BS2 cannot be met. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD
  • no healthy adult carriers have been observed.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Well-established functional studies (PMID:30531871, PMID:28487443) demonstrate that p.Leu755Ser has a gain-of-function, activating effect on ERBB2 kinase activity and downstream signaling. BS3 requires functional studies showing no damaging effect; the available evidence contradicts BS3. Details ▾Hide ▴
Evidence considered
  • PMID:30531871: L755S is an activating mutation
  • conferring endocrine resistance and hyperactivating ERK/AKT signaling.
  • PMID:28487443: L755S identified as a mechanism of acquired resistance to HER2-targeted therapy.
  • All functional evidence points to a gain-of-function effect
  • opposite of what BS3 requires.
Sources
PMID:30531871 ↗3053187128487443
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. Although ERBB2 loss-of-function is a recognized germline disease mechanism, the variant lies in a well-characterized functional hotspot with established gain-of-function effects. Missense variants at this residue are known to be activating in somatic contexts and cannot be dismissed by BP1. Details ▾Hide ▴
Evidence considered
  • ERBB2 germline disease mechanism includes loss-of-function
  • however
  • kinase domain missense mutations have demonstrated gain-of-function effects.
  • Residue 755 is a statistically significant hotspot
  • inconsistent with a benign missense assumption.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder has been reported. BP2 is not supported by available evidence. Details ▾Hide ▴
Evidence considered
  • No in trans observations reported for this variant.
BP4 REVEL score of 0.86 predicts a damaging effect. SpliceAI predicts no splice impact (max delta 0.02) but this is neutral for a missense variant. The available in silico evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.86 (damaging prediction
  • contradictory to BP4).
  • SpliceAI: max delta 0.02 (no splice impact
  • neutral).
Sources
revelspliceai ↗
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. BP5 cannot be applied. Details ▾Hide ▴
Still missing
  • No case with an alternate molecular diagnosis carrying this variant has been reported.
BP6 No reputable source has classified this variant as benign. ClinVar has zero submissions for this variant, and OncoKB classifies it as Oncogenic, not benign. Details ▾Hide ▴
Evidence considered
  • ClinVar variation ID 376035: zero submissions
  • no benign classification.
Sources
clinvar ↗
PS5 No de novo occurrence of this variant with confirmed paternity or maternity has been reported. Same evidence gap as PS2/PM6. Details ▾Hide ▴
Evidence considered
  • No de novo germline observations with confirmed parentage were identified.
Still missing
  • No trio-based sequencing with confirmed parentage is available for this variant.

Not assessed · 2 · no assessment recorded

PP4 No patient phenotype or family history data was provided with this case. PP4 requires a phenotype highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical context. Details ▾Hide ▴
Still missing
  • Patient phenotype information is required to assess PP4.
BS4 No co-segregation data are available for this variant in affected families. BS4 cannot be evaluated without family-based linkage or segregation analysis. Details ▾Hide ▴
Still missing
  • No family segregation studies for ERBB2 L755S have been published.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution (NM_004448.4:c.2264T>C, p.Leu755Ser) and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798. Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 19 of ERBB2.
  • Not a null variant (nonsense
  • frameshift
  • or canonical splice site).
  • Variant bucket: other — generic PVS1 framework not applied.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This is a missense variant (c.2264T>C, p.Leu755Ser) and does not meet the synonymous criterion for BP7. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Identifiers

Gene
ERBB2
Transcript
NM_004448.4
Coding (HGVS c.)
NM_004448.4:c.2264T>C
Protein (HGVS p.)
NP_004439.2:p.(Leu755Ser)
GRCh38
chr17:39723967 T>C
GRCh37
chr17:37880220 T>C
ClinVar
376035
COSMIC
COSV54062780

Gene diagram

Every interpreted variant in ERBB2, mapped onto the exon structure of NM_004448.4. Select a row to find it on the plot.

ERBB2NM_004448.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +329 bp
0.000
SpliceAI acceptor gainat -387 bp
0.000
SpliceAI donor lossat +98 bp
0.020
SpliceAI donor gainat -349 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.040

Other predictors

REVEL
0.860
BayesDel
0.313

How the predictions were used

PP3 SupportingIn silico meta-predictor REVEL gives a score of 0.86, above the 0.5 threshold, supporting a deleterious effect. BayesDel is intermediate (0.313). SpliceAI predicts no splice impact (max delta 0.02), which is neutral for a missense variant. The REVEL score supports PP3 at the supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.86 (damaging).
  • BayesDel score: 0.313 (intermediate
  • non-contributory).
  • SpliceAI max delta: 0.02 (no predicted splice impact).
Still missing
  • Additional in silico predictors (e.g.
  • CADD
  • PolyPhen-2
  • SIFT) were not computed.
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.86 predicts a damaging effect. SpliceAI predicts no splice impact (max delta 0.02) but this is neutral for a missense variant. The available in silico evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.86 (damaging prediction
  • contradictory to BP4).
  • SpliceAI: max delta 0.02 (no splice impact
  • neutral).
Sources
revelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This is a missense variant (c.2264T>C, p.Leu755Ser) and does not meet the synonymous criterion for BP7. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.86. BayesDel score = 0.312741.

8 paper records listed. 1 cited in the classification.

Cited in the classification

  • Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.
    Nayar U et al. · 2019 Feb
    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.
    → PS3 Names this variant
    PMID 30531871 ↗
    Source detail
    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

Other recorded publications

  • Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib.
    Kancha RK et al. · 2011
    No paper-specific finding is recorded.
    PMID 22046346 ↗
  • EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation.
    No paper-specific finding is recorded.
    PMID 18413839 ↗
  • Activating HER2 mutations in HER2 gene amplification negative breast cancer.
    No paper-specific finding is recorded.
    PMID 23220880 ↗
  • Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
    No paper-specific finding is recorded.
    PMID 26619011 ↗
  • HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
    No paper-specific finding is recorded.
    PMID 29420467 ↗
  • Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.
    No paper-specific finding is recorded.
    PMID 30314968 ↗
  • American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
    Cooley LD et al. · 2013
    No paper-specific finding is recorded.
    PMID 23619274 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54062780, n = 173 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.