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).1 The variant is absent from ClinVar with no submissions or classifications reported.2 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.3 OncoKB reports no variant-specific functional evidence (Unknown Oncogenic Effect) and no publications were identified that mention this variant.4 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).5
ERBB2
Final classification
VUS
ERBB2 c.2506C>A · p.Leu836Met
ERBB2
NM_004448.3:c.2506C>A (p.Leu836Met) is a missense variant in exon 21 of ERBB2.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
ERBB2 c.2506C>A
PM2
→
VUS
Gene diagram
· NM_004448.3 · variants mapped to exon structure
ERBB2
NM_004448.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%).
Absent from gnomAD v2.1 (exomes)v4.1 (exomes/genomes)and gnomAD-Canada v1.0 (HostSeq genomes).
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or prevalence data are available to demonstrate enrichment of this variant in affected individuals versus controls.
PM1
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.
PM5
No pathogenic missense variant at codon 836 has been identified as a comparator.
PM6
No de novo occurrence has been reported for this variant.
PP1
No co-segregation data are available.
PP2
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.
PP3
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).
PP4
No patient phenotype or family history data are available to assess phenotypic specificity for an ERBB2-related disorder.
PP5
No reputable source has classified this variant.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from population databases.
BS2
No observation of this variant in healthy adult controls has been documented.
BS3
No functional studies demonstrating a neutral or benign effect have been identified for this variant.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP1
ERBB2 is a receptor tyrosine kinase in which both truncating and missense variants are implicated in disease.
BP2
No observations of this variant in trans with a known pathogenic variant have been reported.
BP4
Computational evidence is conflicting and does not provide multiple concordant lines supporting a benign effect.
BP5
No case has been identified in which this variant is found alongside an alternate molecular basis for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 3
PVS1 · PS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.74. BayesDel score = 0.209718.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERBB2, a receptor tyrosine kinase, is altered by mutation, amplification and/or overexpression in various cancer types, most frequently in breast, eso
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links