This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 489 of the ERBB2 protein (p.Pro489Leu). This variant is present in population databases (rs142456637, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 134071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERBB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_004448.4(ERBB2):c.1466C>T (p.Pro489Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004448.4(ERBB2):c.1466C>T (p.Pro489Leu)
Variation ID: 134071 Accession: VCV000134071.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q12 17: 39715892 (GRCh38) [ NCBI UCSC ] 17: 37872145 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Aug 18, 2024 Dec 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004448.4:c.1466C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004439.2:p.Pro489Leu missense NM_001005862.1:c.1376C>T NM_001005862.3:c.1376C>T NP_001005862.1:p.Pro459Leu missense NM_001289936.2:c.1421C>T NP_001276865.1:p.Pro474Leu missense NM_001289937.2:c.1466C>T NP_001276866.1:p.Pro489Leu missense NM_001289938.2:c.1376C>T NP_001276867.1:p.Pro459Leu missense NM_001382782.1:c.1376C>T NP_001369711.1:p.Pro459Leu missense NM_001382783.1:c.1376C>T NP_001369712.1:p.Pro459Leu missense NM_001382784.1:c.1583C>T NP_001369713.1:p.Pro528Leu missense NM_001382785.1:c.1466C>T NP_001369714.1:p.Pro489Leu missense NM_001382786.1:c.1583C>T NP_001369715.1:p.Pro528Leu missense NM_001382787.1:c.1541C>T NP_001369716.1:p.Pro514Leu missense NM_001382788.1:c.1466C>T NP_001369717.1:p.Pro489Leu missense NM_001382789.1:c.1487C>T NP_001369718.1:p.Pro496Leu missense NM_001382790.1:c.1466C>T NP_001369719.1:p.Pro489Leu missense NM_001382791.1:c.1457C>T NP_001369720.1:p.Pro486Leu missense NM_001382792.1:c.1466C>T NP_001369721.1:p.Pro489Leu missense NM_001382793.1:c.1466C>T NP_001369722.1:p.Pro489Leu missense NM_001382794.1:c.1466C>T NP_001369723.1:p.Pro489Leu missense NM_001382795.1:c.1466C>T NP_001369724.1:p.Pro489Leu missense NM_001382796.1:c.1466C>T NP_001369725.1:p.Pro489Leu missense NM_001382797.1:c.1466C>T NP_001369726.1:p.Pro489Leu missense NM_001382798.1:c.1466C>T NP_001369727.1:p.Pro489Leu missense NM_001382799.1:c.1286C>T NP_001369728.1:p.Pro429Leu missense NM_001382800.1:c.1466C>T NP_001369729.1:p.Pro489Leu missense NM_001382801.1:c.1466C>T NP_001369730.1:p.Pro489Leu missense NM_001382802.1:c.1208C>T NP_001369731.1:p.Pro403Leu missense NM_001382803.1:c.1466C>T NP_001369732.1:p.Pro489Leu missense NM_001382804.1:c.638C>T NP_001369733.1:p.Pro213Leu missense NM_001382805.1:c.1466C>T NP_001369734.1:p.Pro489Leu missense NM_001382806.1:c.1222+533C>T intron variant NR_110535.2:n.1704C>T non-coding transcript variant NC_000017.11:g.39715892C>T NC_000017.10:g.37872145C>T NG_007503.1:g.32753C>T LRG_724:g.32753C>T LRG_724t2:c.1466C>T LRG_724p2:p.Pro489Leu - Protein change
- P459L, P489L, P474L, P213L, P403L, P429L, P486L, P496L, P514L, P528L
- Other names
- -
- Canonical SPDI
- NC_000017.11:39715891:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
The Genome Aggregation Database (gnomAD) 0.00069
Exome Aggregation Consortium (ExAC) 0.00077
The Genome Aggregation Database (gnomAD), exomes 0.00077
Trans-Omics for Precision Medicine (TOPMed) 0.00089
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ERBB2 | - | - |
GRCh38 GRCh37 |
679 | 694 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
Sep 19, 2013 | RCV000120740.8 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 27, 2023 | RCV001048437.16 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011251.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Uncertain significance
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001212443.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 489 of the ERBB2 protein (p.Pro489Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 489 of the ERBB2 protein (p.Pro489Leu). This variant is present in population databases (rs142456637, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 134071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERBB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005192836.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084903.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
Comment:
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 489 of the ERBB2 protein (p.Pro489Leu). This variant is present in population databases (rs142456637, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 134071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERBB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. | Aloraifi F | The FEBS journal | 2015 | PMID: 26094658 |
Text-mined citations for rs142456637 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.