Genetic Variant NM_005228.5:c.2312_2314dupACC (chr7-55181320-A-AACC) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_005228.5(EGFR):c.2312_2314dupACC(p.Asn771_Pro772insHis) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P772P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Consequence

EGFR
NM_005228.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.47

Publications

1 publications found

Variant links:

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

EGFR links:

EGFR-AS1 (HGNC:40207): (EGFR antisense RNA 1)

EGFR-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 27 uncertain in NM_005228.5

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_005228.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 7-55181320-A-AACC is Pathogenic according to our data. Variant chr7-55181320-A-AACC is described in ClinVar as Pathogenic. ClinVar VariationId is 45258.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGFR	NM_005228.5	MANE Select	c.2312_2314dupACC	p.Asn771_Pro772insHis	disruptive_inframe_insertion	Exon 20 of 28	NP_005219.2
EGFR	NM_001346899.2		c.2177_2179dupACC	p.Asn726_Pro727insHis	disruptive_inframe_insertion	Exon 19 of 27	NP_001333828.1
EGFR	NM_001346900.2		c.2153_2155dupACC	p.Asn718_Pro719insHis	disruptive_inframe_insertion	Exon 20 of 28	NP_001333829.1	C9JYS6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2312_2314dupACC	p.Asn771_Pro772insHis	disruptive_inframe_insertion	Exon 20 of 28	ENSP00000275493.2	P00533-1
EGFR	ENST00000455089.5	TSL:1	c.2177_2179dupACC	p.Asn726_Pro727insHis	disruptive_inframe_insertion	Exon 19 of 26	ENSP00000415559.1	Q504U8
EGFR	ENST00000898199.1		c.2303_2305dupACC	p.Asn768_Pro769insHis	disruptive_inframe_insertion	Exon 20 of 28	ENSP00000568258.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Non-small cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over