Submissions for variant NM_007294.4(BRCA1):c.1912G>A (p.Glu638Lys)

dbSNP: rs80357005

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000776222	SCV000911411	likely benign	Hereditary cancer-predisposing syndrome	2016-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001307829	SCV001497255	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-25	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 37433). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 30254663). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 638 of the BRCA1 protein (p.Glu638Lys).
Mendelics	RCV002247401	SCV002516980	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000776222	SCV002720579	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	The p.E638K variant (also known as c.1912G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1912. The glutamic acid at codon 638 is replaced by lysine, an amino acid with similar properties. In one study, this alteration was detected in one family from a cohort of 1045 Italian patients who met BRCA1/2 testing criteria (Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000776222	SCV003849642	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).
Sharing Clinical Reports Project (SCRP)	RCV000031014	SCV000053607	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031014	SCV000144246	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-05-21	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000031014	SCV000189890	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031014	SCV004228337	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)