rs28933369

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP2 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G776V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 2.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004448.4
• 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 id is 44990.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB2. . Gene score misZ 3.2497 (greater than the threshold 3.09). Trascript score misZ 4.234 (greater than threshold 3.09). GenCC has associacion of gene with visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.
• PP5: Variant 17-39724744-G-A is Pathogenic according to our data. Variant chr17-39724744-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id 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/exons	MANE	UniProt
ERBB2	NM_004448.4	c.2326G>A	p.Gly776Ser	missense_variant	20/27	ENST00000269571.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB2	ENST00000269571.10	c.2326G>A	p.Gly776Ser	missense_variant	20/27	1	NM_004448.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 30, 2004

- -

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

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