NM_004448.3:c.2873G>C

ERBB2 · NP_004439.2:p.(Cys958Ser) · NM_004448.3

GRCh37: chr17:37882815 G>C · GRCh38: chr17:39726562 G>C

Gene: ERBB2 Transcript: NM_004448.3

Final call

VUS

PM2 moderate

Variant details

Gene

ERBB2

Transcript

NM_004448.3

Protein

NP_004439.2:p.(Cys958Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.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).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No prior pathogenic variant with the same amino acid change (p.Cys958Ser) has been identified in ClinVar or the published literature.	clinvar
PS2	Not met	No de novo data are available for NM_004448.3:c.2873G>C.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or prevalence data are available for this variant in affected individuals.
PS5	Not met	No reputable source has reported NM_004448.3:c.2873G>C as pathogenic. This variant is absent from ClinVar.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic variant at the same residue (Cys958) has been identified in ClinVar to satisfy PM5 comparator requirements.	clinvar pm5_candidates
PM6	Not met	No de novo evidence is available for NM_004448.3:c.2873G>C.
PP1	Not met	No co-segregation data are available for this variant.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for ERBB2-related disease.
PP5	Not met	No reputable source has reported NM_004448.3:c.2873G>C as likely pathogenic. This variant is absent from ClinVar.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	NM_004448.3:c.2873G>C is absent from gnomAD. The allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	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	Not met	No well-established functional studies showing no deleterious effect have been identified for NM_004448.3:c.2873G>C.	oncokb
BS4	Not met	No segregation data are available for this variant.
BP1	Not met	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.
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic dominant ERBB2 variant.
BP3	N/A	NM_004448.3:c.2873G>C is a missense variant, not an in-frame deletion/insertion in a repetitive region.
BP4	Not met	REVEL score of 0.905 predicts a deleterious effect. Computational evidence does not support a benign interpretation; rather, it supports potential pathogenicity.	revel bayesdel spliceai
BP5	Not met	No evidence of an alternative molecular basis for disease in a case harboring this variant.
BP6	Not met	No reputable source has classified NM_004448.3:c.2873G>C as benign or likely benign. This variant is absent from ClinVar.	clinvar
BP7	N/A	NM_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.	spliceai

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