17-39727704-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004448.4(ERBB2):c.3428C>T(p.Pro1143Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,402,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1143T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 0.283

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027276695).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000114 (16/1402416) while in subpopulation SAS AF = 0.000206 (16/77732). AF 95% confidence interval is 0.000128. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 16 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.3428C>T	p.Pro1143Leu	missense_variant	Exon 27 of 27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10 link	c.3428C>T	p.Pro1143Leu	missense_variant	Exon 27 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000981

AC:

AN:

203916

AF XY:

0.0000183

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1402416

Hom.:

Cov.:

AF XY:

0.0000202

AC XY:

AN XY:

692162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31470

American (AMR)

AF:

0.00

AC:

AN:

35074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21774

East Asian (EAS)

AF:

0.00

AC:

AN:

39254

South Asian (SAS)

AF:

0.000206

AC:

AN:

77732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082876

Other (OTH)

AF:

0.00

AC:

AN:

57638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Feb 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3428C>T (p.P1143L) alteration is located in exon 27 (coding exon 27) of the ERBB2 gene. This alteration results from a C to T substitution at nucleotide position 3428, causing the proline (P) at amino acid position 1143 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1143 of the ERBB2 protein (p.Pro1143Leu). This variant is present in population databases (rs587778269, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ERBB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134081). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.24

.;.;.;T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.76

.;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;.;.;L

PhyloP100

0.28

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.26

.;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.31

.;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.017, 0.0010

.;.;B;B;B

Vest4

0.055

MutPred

0.15

.;.;.;.;Loss of relative solvent accessibility (P = 0.0981);

MVP

0.75

MPC

0.35

ClinPred

0.036

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.12

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over