rs28933369

Variant names:

• chr17-39724744-G-A
• rs28933369
• NM_004448.4:c.2326G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39724744-G-A
• chr17-39724744-G-C
• chr17-39724744-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_004448.4(ERBB2):​c.2326G>A​(p.Gly776Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G776delinsCC) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.91
• Publications: 52 publications found

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)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-39724744-G-TTAT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 44990.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 17-39724744-G-A is Pathogenic according to our data. Variant chr17-39724744-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13879.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2444601). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.2326G>A	p.Gly776Ser	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.2326G>A	p.Gly776Ser	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gastric cancer Pathogenic:1

Sep 30, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.37	.;.;.;T;.;T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.63	.;.;.;.;.;N
PhyloP100		2.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.4	.;N;N;N;.;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	.;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		1.0, 0.49	.;.;D;P;.;P
Vest4		0.39
MutPred		0.35		.;.;.;.;Loss of catalytic residue at A775 (P = 0.2198);Loss of catalytic residue at A775 (P = 0.2198);
MVP		0.87
MPC		2.3
ClinPred		0.61	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs28933369; hg19: chr17-37880997; COSMIC: COSV54066483; COSMIC: COSV54066483;