Submissions for variant NM_007294.4(BRCA1):c.1662G>C (p.Glu554Asp)

dbSNP: rs876659028

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213495	SCV000274992	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The p.E554D variant (also known as c.1662G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1662. The glutamic acid at codon 554 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703330	SCV000832227	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-27	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: 231215). This variant is also known as c.1781G>C. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 554 of the BRCA1 protein (p.Glu554Asp).
Color Diagnostics, LLC DBA Color Health	RCV000213495	SCV001356044	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 554 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527044	SCV001737875	uncertain significance	not specified	2021-06-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1662G>C (p.Glu554Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250846 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1662G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001762483	SCV002001001	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer in published literature (Abdel-Razeq et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1781G>C; This variant is associated with the following publications: (PMID: 35402282, 15343273, 31911673, 29884841, 33712364, 32377563)
Fulgent Genetics, Fulgent Genetics	RCV002503869	SCV002815816	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000213495	SCV003851137	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003233502	SCV003930440	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-14	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the BRCA1 gene (c.1662G>C).This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 554 of the BRCA1 protein (p.Glu554Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is also known as c.1781G>C. ClinVar contains an entry for this variant (Variation ID: 231215). This amino acid position is not conserved (PhyloP=0.8) . In silico analysis supports that this missense variant has a deleterious effect on protein structure/function based on Sift , PolyPhen, MVP, Mutation assessor, M-Cap , FATHMM, BayesDel and MetaLR . 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.