rs1131692237

Positions:

• chr17-39725161-T-A
• chr17-39725161-T-C
• chr17-39725161-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_004448.4(ERBB2):​c.2606T>A​(p.Leu869Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L869R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

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 9 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity ERBB2_HUMAN there are 28 pathogenic changes around while only 4 benign (88%) 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 chr17-39725161-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 431024.Status of the report is no_assertion_criteria_provided, 0 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB2	NM_004448.4	c.2606T>A	p.Leu869Gln	missense_variant	21/27	ENST00000269571.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB2	ENST00000269571.10	c.2606T>A	p.Leu869Gln	missense_variant	21/27	1	NM_004448.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Benign	0.94
DEOGEN2	Uncertain	0.75	.;.;.;D;.;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.3	.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.3	.;D;D;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 0.99, 1.0	.;.;D;D;.;D
Vest4		0.91
MutPred		0.56		.;.;.;.;Loss of stability (P = 0.0126);Loss of stability (P = 0.0126);
MVP		0.97
MPC		2.5
ClinPred		0.93	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-37881414; COSMIC: COSV54087312; COSMIC: COSV54087312;