17-39724747-G-T

Variant names:

• chr17-39724747-G-T
• rs121913471
• NM_004448.4:c.2329G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ERBB2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 3.2497 (above the threshold of 3.09). Trascript score misZ: 4.234 (above the threshold of 3.09). GenCC associations: The gene is linked to visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.2329G>T	p.Val777Leu	missense_variant	Exon 20 of 27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.2329G>T	p.Val777Leu	missense_variant	Exon 20 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

Revision: criteria provided, single submitter

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	.;.;.;T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	.;.;.;.;.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.97	.;N;N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.48	.;T;T;T;.;T
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0010, 0.0030, 0.0080	.;.;B;B;.;B
Vest4		0.82
MutPred		0.54		.;.;.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.92
MPC		1.2
ClinPred		0.70	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs121913471; hg19: chr17-37881000; COSMIC: COSV54062767; COSMIC: COSV54062767;