Submissions for variant NM_007294.4(BRCA1):c.1253A>C (p.Glu418Ala)

gnomAD frequency: 0.00002  dbSNP: rs1555592050

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000576146	SCV000665930	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-19	criteria provided, single submitter	clinical testing	The p.E418A variant (also known as c.1253A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 1253. The glutamic acid at codon 418 is replaced by alanine, an amino acid with dissimilar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819564	SCV000960231	benign	Hereditary breast ovarian cancer syndrome	2024-08-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000576146	SCV003846072	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx	RCV003228959	SCV003925953	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Lerner-Ellis et al., 2021); Also known as 1372A>C; This variant is associated with the following publications: (PMID: 25348012, 31911673, 32885271, 20215511, 10426999, 9582019, 9926942, 15343273)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357547	SCV001553047	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu418Ala variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Glu418 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the Breast cancer type 1 susceptibility protein (BRCA1) functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.