Submissions for variant NM_005228.5(EGFR):c.2885G>A (p.Arg962His)

gnomAD frequency: 0.00009  dbSNP: rs144496976

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000709017	SCV000838218	likely benign	Hereditary cancer	2024-04-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054589	SCV001218932	uncertain significance	EGFR-related lung cancer	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 962 of the EGFR protein (p.Arg962His). This variant is present in population databases (rs144496976, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer, osteosarcoma, non-Hodgkin lymphoma, and nodular sclerosis Hodgkin lymphoma (PMID: 32191290, 34308104, 35264596). ClinVar contains an entry for this variant (Variation ID: 134027). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EGFR protein function with a positive predictive value of 80%. 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.
GeneDx	RCV004724815	SCV005332697	uncertain significance	not provided	2023-12-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 34308104, 35264596, 32191290, 35957908, 29641532)
Ambry Genetics	RCV004948190	SCV005579568	likely benign	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV005042225	SCV005668428	uncertain significance	Inflammatory skin and bowel disease, neonatal, 2; Lung cancer	2024-03-13	criteria provided, single submitter	clinical testing
ITMI	RCV000120696	SCV000084857	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003975068	SCV004788798	uncertain significance	EGFR-related disorder	2023-12-19	no assertion criteria provided	clinical testing	The EGFR c.2885G>A variant is predicted to result in the amino acid substitution p.Arg962His. This variant has been reported in multiple individuals with breast cancer, osteosarcoma, and diffuse large B cell lymphoma (see for example, Table S3, Guindalini et al. 2022. PubMed ID: 35264596; Table S5, Mirabello et al. 2020. PubMed ID: 32191290; search 55268045 in Table S2, Kim et al. 2021. PubMed ID: 34308104). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD. This variant has been classified as a variant of uncertain significance by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.