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).1 PVS1 is not applicable as this is a missense variant, not a null variant (nonsense, frameshift, or canonical splice).2 No ClinVar classifications, no functional studies, no segregation data, and no case-control evidence are available for this variant.3 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 2015.4 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).5
ERBB2
Final classification
VUS
ERBB2 c.2873G>C · p.Cys958Ser
ERBB2
NM_004448.3:c.2873G>C (p.Cys958Ser) is a missense variant in exon 24 of ERBB2, located within the protein tyrosine kinase domain.
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.
Classification rationale
PM2
VUS
ERBB2 c.2873G>C
PM2
→
VUS
2
pvs1_variant_assessmentpvs1_generic_framework ↗
4
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_004448.3 · variants mapped to exon structure
ERBB2
NM_004448.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
Assessed · not applied
Pathogenic
PS1
No prior pathogenic variant with the same amino acid change (p.Cys958Ser) has been identified in ClinVar or the published literature.
PS2
No de novo data are available for NM_004448.3:c.2873G>C.
PS3
No well-established functional studies have been identified for NM_004448.3:c.2873G>C.
PS4
No case-control or prevalence data are available for this variant in affected individuals.
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).
PM5
No pathogenic variant at the same residue (Cys958) has been identified in ClinVar to satisfy PM5 comparator requirements.
PM6
No de novo evidence is available for NM_004448.3:c.2873G>C.
PP1
No co-segregation data are available for this variant.
PP2
HCI prior scores are not available for ERBB2.
PP3
REVEL score of 0.905 predicts a deleterious effect, but BayesDel (0.477) is intermediate and SpliceAI (0.00) shows no splicing impact.
PP4
No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for ERBB2-related disease.
PP5
No reputable source has reported NM_004448.3:c.2873G>C as likely pathogenic.
Benign
BA1
NM_004448.3:c.2873G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_004448.3:c.2873G>C is absent from gnomAD.
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.
BS3
No well-established functional studies showing no deleterious effect have been identified for NM_004448.3:c.2873G>C.
BS4
No segregation data are available for this variant.
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.
BP2
No evidence that this variant has been observed in trans with a known pathogenic dominant ERBB2 variant.
BP4
REVEL score of 0.905 predicts a deleterious effect.
BP5
No evidence of an alternative molecular basis for disease in a case harboring this variant.
BP6
No reputable source has classified NM_004448.3:c.2873G>C as benign or likely benign.
N/A · 3
PVS1 · BP3 · 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 = 0.905. BayesDel score = 0.476639.
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