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ERBB2c.2873G>CUncertain significance
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Variant interpretation report

ERBB2 c.2873G>C, p.(Cys958Ser)

NM_004448.3:c.2873G>C NP_004439.2:p.(Cys958Ser) View identifiers
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.

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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

NM_004448.3:c.2873G>C is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating this variant is extremely rare in the general population.

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 moderate; combination = 1 moderate, 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.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

27 criteria with recorded statuses: 1 met · 23 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_004448.3:c.2873G>C (p.Cys958Ser) is a missense variant in exon 24 of ERBB2, located within the protein tyrosine kinase domain.

This variant is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (PM2).

PVS1 is not applicable as this is a missense variant, not a null variant (nonsense, frameshift, or canonical splice).

No ClinVar classifications, no functional studies, no segregation data, and no case-control evidence are available for this variant.

REVEL in silico prediction is 0.905 (deleterious), but BayesDel (0.477) is intermediate and SpliceAI (0.00) shows no splicing impact. PP3 is not met as multiple concordant computational lines are required under generic ACMG/AMP 2015.

No publications were identified that mention NM_004448.3:c.2873G>C (p.Cys958Ser). Five gene-level papers were reviewed and none contained variant-specific evidence.

Overall, with one moderate criterion (PM2) met and no other criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework (PMID:25741868).

Met · 1

PM2 ModerateNM_004448.3:c.2873G>C is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating this variant is extremely rare in the general population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 23 · evaluated, threshold not reached

PS1 No prior pathogenic variant with the same amino acid change (p.Cys958Ser) has been identified in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no pathogenic comparator with the same amino acid change
Still missing
  • No clinical reports of a pathogenic Cys958Ser change
Sources
clinvar ↗
PS2 No de novo data are available for NM_004448.3:c.2873G>C. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation data
PS3 No well-established functional studies have been identified for NM_004448.3:c.2873G>C. OncoKB classifies this variant as 'Unknown Oncogenic Effect' without variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence
Still missing
  • No in vitro or in vivo functional studies available for this variant
Sources
oncokb ↗
PS4 No case-control or prevalence data are available for this variant in affected individuals. Details ▾Hide ▴
Still missing
  • No affected vs. control population data
PM1 Residue Cys958 lies within the protein tyrosine kinase domain of ERBB2, but it has not been identified as a statistically significant mutational hot spot (Cancer Hotspots negative). Without VCEP-specific domain criteria for ERBB2, PM1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no significant hotspot at residue Cys958
Still missing
  • No ERBB2 VCEP domain-level PM1 criteria available
PM5 No pathogenic variant at the same residue (Cys958) has been identified in ClinVar to satisfy PM5 comparator requirements. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants in ClinVar
Sources
clinvar ↗pm5_candidates
PM6 No de novo evidence is available for NM_004448.3:c.2873G>C. Details ▾Hide ▴
Still missing
  • No de novo confirmation data
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data
PP2 HCI prior scores are not available for ERBB2. Without this metric or VCEP-specified thresholds, the low rate of benign missense variation in this gene cannot be established for PP2 application. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for ERBB2
Still missing
  • No ERBB2 VCEP PP2 criteria
  • HCI prior data unavailable
PP3 REVEL score of 0.905 predicts a deleterious effect, but BayesDel (0.477) is intermediate and SpliceAI (0.00) shows no splicing impact. Under generic ACMG/AMP 2015, PP3 requires multiple lines of computational evidence supporting a deleterious effect; only REVEL provides supportive evidence here. Details ▾Hide ▴
Evidence considered
  • REVEL 0.905 (deleterious)
  • BayesDel 0.477 (intermediate
  • below pathogenic threshold)
  • SpliceAI max delta 0.00 (no splice impact)
Still missing
  • Insufficient concordance across in silico predictors to satisfy PP3
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for ERBB2-related disease. Details ▾Hide ▴
Still missing
  • No clinical phenotype data provided
PP5 No reputable source has reported NM_004448.3:c.2873G>C as likely pathogenic. This variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no classification available
Sources
clinvar ↗
BA1 NM_004448.3:c.2873G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF = 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_004448.3:c.2873G>C is absent from gnomAD. The allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF = 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No evidence that NM_004448.3:c.2873G>C has been observed in healthy adult controls, either homozygous or in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
  • No data on observation in healthy controls
BS3 No well-established functional studies showing no deleterious effect have been identified for NM_004448.3:c.2873G>C. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies identified
Still missing
  • No functional studies available
Sources
oncokb ↗
BS4 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data
BP1 Germline disease association for ERBB2 is not well-characterized as being caused primarily by truncating variants; missense variants in the kinase domain are a known pathogenic mechanism in somatic contexts. BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ERBB2 is not established as a gene where primarily truncating variants cause germline disease
BP2 No evidence that this variant has been observed in trans with a known pathogenic dominant ERBB2 variant. Details ▾Hide ▴
Still missing
  • No trans observation data
BP4 REVEL score of 0.905 predicts a deleterious effect. Computational evidence does not support a benign interpretation; rather, it supports potential pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.905 (deleterious)
  • computational evidence argues against BP4
Sources
revelbayesdelspliceai ↗
BP5 No evidence of an alternative molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No clinical cases with alternative diagnoses
BP6 No reputable source has classified NM_004448.3:c.2873G>C as benign or likely benign. This variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
PS5 No reputable source has reported NM_004448.3:c.2873G>C as pathogenic. This variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no classification by any submitter
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004448.3:c.2873G>C is a missense substitution (p.Cys958Ser) in exon 24. This does not fall into the null variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) defined by the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant p.Cys958Ser
  • not a null variant
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP3 N/ANM_004448.3:c.2873G>C is a missense variant, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP3 applies to in-frame indels in repetitive regions
BP7 N/ANM_004448.3:c.2873G>C is a missense variant (p.Cys958Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous variants only
Sources
spliceai ↗

Identifiers

Gene
ERBB2
Transcript
NM_004448.3
Coding (HGVS c.)
NM_004448.3:c.2873G>C
Protein (HGVS p.)
NP_004439.2:p.(Cys958Ser)
GRCh38
chr17:39726562 G>C
GRCh37
chr17:37882815 G>C

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…
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

Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.040

Other predictors

REVEL
0.905
BayesDel
0.477

How the predictions were used

PP3 REVEL score of 0.905 predicts a deleterious effect, but BayesDel (0.477) is intermediate and SpliceAI (0.00) shows no splicing impact. Under generic ACMG/AMP 2015, PP3 requires multiple lines of computational evidence supporting a deleterious effect; only REVEL provides supportive evidence here. Details ▾Hide ▴
Evidence considered
  • REVEL 0.905 (deleterious)
  • BayesDel 0.477 (intermediate
  • below pathogenic threshold)
  • SpliceAI max delta 0.00 (no splice impact)
Still missing
  • Insufficient concordance across in silico predictors to satisfy PP3
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.905 predicts a deleterious effect. Computational evidence does not support a benign interpretation; rather, it supports potential pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.905 (deleterious)
  • computational evidence argues against BP4
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_004448.3:c.2873G>C is a missense variant (p.Cys958Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous variants only
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.905. BayesDel score = 0.476639.

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

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 = 0.905. BayesDel score = 0.476639.

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.