NM_004448.4:c.2264T>C

ERBB2 · NP_004439.2:p.(Leu755Ser) · NM_004448.4

GRCh37: chr17:37880220 T>C · GRCh38: chr17:39723967 T>C

Gene: ERBB2 Transcript: NM_004448.4

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Leu755Ser)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	This 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	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.
PS3	Met	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.	PMID:30531871 oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not met	No de novo occurrence of this variant with confirmed paternity or maternity has been reported. Same evidence gap as PS2/PM6.
PM1	Met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo germline observation of this variant has been reported, with or without confirmed parentage. Same evidence gap as PS2.
PP1	Not met	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.
PP2	Not met	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.	pvs1_gene_context
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	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.	clinvar oncokb
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). BA1 requires allele frequency >1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1. BS1 requires allele frequency >0.3% in population databases.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	PMID:30531871
BS4	Not assessed	No co-segregation data are available for this variant in affected families. BS4 cannot be evaluated without family-based linkage or segregation analysis.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Not met	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.	revel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease. BP5 cannot be applied.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar has zero submissions for this variant, and OncoKB classifies it as Oncogenic, not benign.	clinvar
BP7	N/A	BP7 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.

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.