17-39724743-TG-TTTAT

Variant names:

• chr17-39724744-G-TTAT
• rs397516980
• NM_004448.4:c.2326delGinsTTAT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM4_Supporting PM5 PP5_Moderate

The NM_004448.4(ERBB2):​c.2326delGinsTTAT​(p.Gly776delinsLeuCys) variant causes a missense, disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). 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, disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.91
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004448.4. Strenght limited to Supporting due to length of the change: 1aa.
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant 17-39724744-G-TTAT is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	NM_004448.4	MANE Select	c.2326delGinsTTAT	p.Gly776delinsLeuCys	missense disruptive_inframe_insertion	Exon 20 of 27	NP_004439.2
	ERBB2	NM_001382784.1		c.2443delGinsTTAT	p.Gly815delinsLeuCys	missense disruptive_inframe_insertion	Exon 21 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.2428delGinsTTAT	p.Gly810delinsLeuCys	missense disruptive_inframe_insertion	Exon 21 of 28	NP_001369714.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.2326delGinsTTAT	p.Gly776delinsLeuCys	missense disruptive_inframe_insertion	Exon 20 of 27	ENSP00000269571.4
	ERBB2	ENST00000584450.5	TSL:1	c.2326delGinsTTAT	p.Gly776delinsLeuCys	missense disruptive_inframe_insertion	Exon 20 of 26	ENSP00000463714.1
	ERBB2	ENST00000578373.5	TSL:1	n.*2116delGinsTTAT		non_coding_transcript_exon	Exon 20 of 27	ENSP00000463427.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1

May 19, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

Other links and lift over

dbSNP: rs397516980; hg19: chr17-37880997; COSMIC: COSV54068502;