NM_004448.3:c.2506C>A

ERBB2 · NP_004439.2:p.(Leu836Met) · NM_004448.3

GRCh37: chr17:37881314 C>A · GRCh38: chr17:39725061 C>A

Gene: ERBB2 Transcript: NM_004448.3

Final call

VUS

PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.3

Protein

NP_004439.2:p.(Leu836Met)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004448.3:c.2506C>A (p.Leu836Met) is a missense variant in exon 21 of ERBB2.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

The variant is absent from ClinVar with no submissions or classifications reported.

In silico predictions are conflicting: REVEL (0.74) supports a deleterious effect, while BayesDel (0.21) does not and SpliceAI predicts no splicing impact (max delta = 0.00). Neither PP3 nor BP4 is met.

OncoKB reports no variant-specific functional evidence (Unknown Oncogenic Effect) and no publications were identified that mention this variant.

No CSPEC/VCEP framework exists for ERBB2; generic ACMG/AMP 2015 criteria were applied per Richards et al. (PMID:25741868). With only one supporting pathogenic criterion (PM2) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_004448.3:c.2506C>A is a missense variant (p.Leu836Met) and does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same codon resulting in the same predicted amino acid change that is already established as pathogenic. This variant is absent from ClinVar and no pathogenic comparators at codon 836 were identified.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. No publications or case-level data report de novo inheritance.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publications or curated sources provide functional data for this variant.	oncokb
PS4	Not met	No case-control or prevalence data are available to demonstrate enrichment of this variant in affected individuals versus controls. The variant is absent from all queried population and clinical databases.
PS5	Not met	No other missense variant at codon 836 has been established as pathogenic. The variant is absent from ClinVar and no literature reports a pathogenic comparator at this residue.	clinvar pm5_candidates
PM1	Not met	The p.Leu836Met substitution lies within the ERBB2 kinase domain, but residue 836 has not been identified as a statistically significant mutational hotspot (cancerhotspots.org) and no VCEP-approved critical domain specification exists for germline ERBB2 interpretation.
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at codon 836 has been identified as a comparator. Automated PM5 candidate harvesting found zero same-residue candidates in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence has been reported for this variant. No publications or database submissions document a de novo observation.
PP1	Not met	No co-segregation data are available. No family studies have been reported for this variant.
PP2	Not assessed	HCI gene-level prior is not available for ERBB2, precluding assessment of missense constraint (z-score) and the proportion of benign missense variation in this gene. PP2 cannot be applied without these metrics.
PP3	Not met	Computational evidence is conflicting: REVEL score (0.74) supports a deleterious effect, but BayesDel (0.209718) is below the typical pathogenic threshold and SpliceAI predicts no splicing impact (max delta = 0.00). Under ACMG/AMP 2015, multiple concordant lines of computational evidence are required, which is not satisfied here.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available to assess phenotypic specificity for an ERBB2-related disorder.
PP5	Not met	No reputable source has classified this variant. The variant is absent from ClinVar with zero submissions, and no expert panel or clinical laboratory has rendered a classification.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from population databases. Allele frequency does not exceed the 0.3% BS1 threshold for a rare disease.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in healthy adult controls has been documented. The variant is absent from all population databases.
BS3	Not met	No functional studies demonstrating a neutral or benign effect have been identified for this variant. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	Not met	ERBB2 is a receptor tyrosine kinase in which both truncating and missense variants are implicated in disease. The germline disease spectrum is not established as exclusively truncation-mediated, and ERBB2 is well-known for activating missense mutations in somatic cancer. BP1 cannot be applied without evidence that only truncating variants cause the relevant germline disorder.	pvs1_gene_context
BP2	Not met	No observations of this variant in trans with a known pathogenic variant have been reported.
BP4	Not met	Computational evidence is conflicting and does not provide multiple concordant lines supporting a benign effect. While SpliceAI predicts no splicing impact (max delta = 0.00) and BayesDel (0.21) leans benign, REVEL (0.74) supports a deleterious effect, precluding a BP4 determination.	revel bayesdel spliceai
BP5	Not met	No case has been identified in which this variant is found alongside an alternate molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar, and no expert panel or clinical laboratory has rendered a benign classification.	clinvar
BP7	N/A	NM_004448.3:c.2506C>A (p.Leu836Met) is a missense variant, not synonymous or intronic; BP7 applies only to silent variants with no predicted splice impact.

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.