About ERBB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERBB2 c.2506C>A, p.(Leu836Met)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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%).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant (allele frequency <0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- v4.1 (exomes/genomes)
- and gnomAD-Canada v1.0 (HostSeq genomes).
Sources
Not met · 21 · evaluated, threshold not reached
PS2 No de novo occurrence data are available for this variant. No publications or case-level data report de novo inheritance. Details ▾Hide ▴
Evidence considered
- No de novo data identified in any source.
Still missing
- No case-level phenotype or parent-of-origin data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No functional assays (in vitro or in vivo) performed for this variant.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- No affected vs. control data available.
Still missing
- No case-count or cohort data available for statistical comparison.
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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- no VCEP domain specification available for ERBB2.
Still missing
- No germline domain-level constraint or functional domain specification for ERBB2.
PM5 No pathogenic missense variant at codon 836 has been identified as a comparator. Automated PM5 candidate harvesting found zero same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidates: 0 same-residue comparators
- no expert panel P/LP classification at this residue.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence has been reported for this variant. No publications or database submissions document a de novo observation. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental testing data available.
PP1 No co-segregation data are available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No pedigree or segregation data available.
Still missing
- No family-based segregation analysis performed.
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). Under ACMG/AMP 2015, multiple concordant lines of computational evidence are required, which is not satisfied here. Details ▾Hide ▴
Evidence considered
- REVEL: 0.74 (deleterious threshold >0.5)
- BayesDel: 0.209718 (below pathogenic threshold)
- SpliceAI: max delta 0.00 (no splice impact).
Still missing
- Conflicting in silico predictions
- REVEL and BayesDel disagree on deleteriousness.
Sources
PP4 No patient phenotype or family history data are available to assess phenotypic specificity for an ERBB2-related disorder. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- No proband phenotype
- family history
- or clinical indication documented.
PP5 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. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all queried population databases
- AF = 0.00.
Sources
BS1 This variant is absent from population databases. Allele frequency does not exceed the 0.3% BS1 threshold for a rare disease. Details ▾Hide ▴
Evidence considered
- Absent from all queried population databases.
Sources
BS2 No observation of this variant in healthy adult controls has been documented. The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
- No healthy control or full-penetrance disease data available.
Still missing
- No case-control data for phenotype-negative individuals.
BS3 No functional studies demonstrating a neutral or benign effect have been identified for this variant. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies showing no deleterious effect.
Still missing
- No functional characterization of p.Leu836Met has been performed.
Sources
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family-based data available.
Still missing
- No multi-generational pedigree analysis.
BP1 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. Details ▾Hide ▴
Evidence considered
- ERBB2 germline disease mechanism not exclusively truncating
- missense variants are known in somatic cancer.
Still missing
- Limited characterization of ERBB2 germline disease spectrum.
Sources
pvs1_gene_context
BP2 No observations of this variant in trans with a known pathogenic variant have been reported. Details ▾Hide ▴
Evidence considered
- No trans phase data available.
Still missing
- No phase information with other ERBB2 variants.
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: 0.00 (no splice impact)
- BayesDel: 0.21 (benign-leaning)
- REVEL: 0.74 (deleterious) — conflicting.
Sources
BP5 No case has been identified in which this variant is found alongside an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No co-occurring pathogenic variant data.
BP6 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. Details ▾Hide ▴
PS5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: absent
- PM5 candidates: 0 same-residue comparators identified.
Sources
clinvar ↗pm5_candidates
Not assessed · 1 · no assessment recorded
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. PP2 cannot be applied without these metrics. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- no missense constraint data available.
Still missing
- ERBB2 not included in HCI prior dataset
- alternative constraint metrics needed.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a predicted null variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 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. Details ▾Hide ▴
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants.
Identifiers
- Gene
- ERBB2
- Transcript
- NM_004448.3
- Coding (HGVS c.)
- NM_004448.3:c.2506C>A
- Protein (HGVS p.)
- NP_004439.2:p.(Leu836Met)
- GRCh38
- chr17:39725061 C>A
- GRCh37
- chr17:37881314 C>A
Gene diagram
Every interpreted variant in ERBB2, mapped onto the exon structure of NM_004448.3. Select a row to find it on the plot.
ERBB2NM_004448.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ERBB2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.740
- BayesDel
- 0.210
How the predictions were used
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). Under ACMG/AMP 2015, multiple concordant lines of computational evidence are required, which is not satisfied here. Details ▾Hide ▴
Evidence considered
- REVEL: 0.74 (deleterious threshold >0.5)
- BayesDel: 0.209718 (below pathogenic threshold)
- SpliceAI: max delta 0.00 (no splice impact).
Still missing
- Conflicting in silico predictions
- REVEL and BayesDel disagree on deleteriousness.
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: 0.00 (no splice impact)
- BayesDel: 0.21 (benign-leaning)
- REVEL: 0.74 (deleterious) — conflicting.
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.74. BayesDel score = 0.209718.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004448.3%3Ac.2506C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37881314-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39725061-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39725061-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004448.3%3Ac.2506…
- OncoKB ↗www.oncokb.org/gene/ERBB2/L836M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERBB2+c.2506C%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
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
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.