17-39724747-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_004448.4(ERBB2):c.2329G>T(p.Val777Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:2

Conservation

PhyloP100: 10.0

Publications

327 publications found

Variant links:

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

ERBB2 Gene-Disease associations (from GenCC):

Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lung cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
glioma susceptibility 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
visceral neuropathy, familial, 2, autosomal recessive
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ERBB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004448.4

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERBB2	NM_004448.4	MANE Select	c.2329G>T	p.Val777Leu	missense	Exon 20 of 27	NP_004439.2
ERBB2	NM_001382784.1		c.2446G>T	p.Val816Leu	missense	Exon 21 of 28	NP_001369713.1
ERBB2	NM_001382785.1		c.2431G>T	p.Val811Leu	missense	Exon 21 of 28	NP_001369714.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.2329G>T	p.Val777Leu	missense	Exon 20 of 27	ENSP00000269571.4
ERBB2	ENST00000584450.5	TSL:1	c.2329G>T	p.Val777Leu	missense	Exon 20 of 26	ENSP00000463714.1
ERBB2	ENST00000578373.5	TSL:1	n.*2119G>T		non_coding_transcript_exon	Exon 20 of 27	ENSP00000463427.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. This variant ha s been observed as a somatic change in lung adenocarcinoma, gastric carcinoma, a nd adenocarcinoma of the rectum (Lee 2006, Bettitta 2006). Other amino acid chan ges (V777M, V777A) at this amino acid position have also been reported as somati c changes (COSMIC). In two individuals with colorecal cancer, a V777 mutation wa s coincidentally identified in a tumor with a G12D mutation in KRAS. The clinica l significance of this variant cannot be determined at this time.

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neurofibroma

Other:1

Feb 06, 2025

NYU Undiagnosed Diseases Program, NYU School of Medicine

Significance:

Review Status:no assertion criteria provided

Collection Method:clinical testing

This classification is based on multiple lines of evidence, including the variant’s absence from the healthy population (gnomAD v4 database), functional studies demonstrating an activating and oncogenic effect on the HER2 protein, observations of this variant in the segmental nerve sheath tumors of other individuals, and detection of the variant in spatially distant neurofibroma samples from an affected individual.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

Eigen

Benign

-0.25

Eigen_PC

Benign

0.079

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.9

PhyloP100

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.97

REVEL

Benign

0.28

Sift

Benign

0.48

Sift4G

Benign

0.43

Polyphen

0.0010

Vest4

0.82

MutPred

0.54

Loss of sheet (P = 0.0817)

MVP

0.92

MPC

1.2

ClinPred

0.70

GERP RS

5.3

Varity_R

0.35

gMVP

0.84

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over