Submissions for variant NM_007294.4(BRCA1):c.3555G>T (p.Glu1185Asp)

dbSNP: rs587779368

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766573	SCV000108666	uncertain significance	not provided	2021-05-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); 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: 22711857, 27535533)
Ambry Genetics	RCV000165151	SCV000215862	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	The p.E1185D variant (also known as c.3555G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3555. The glutamic acid at codon 1185 is replaced by aspartic acid, an amino acid with highly similar properties. In one study, this variant was observed in 1/1001 patients with non-mucinous ovarian carcinoma and classified as a variant of unknown significance by the authors (Alsop K et al. J Clin Oncol. 2012 Jul 20;30(21):2654-63). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000469806	SCV000549379	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1185 of the BRCA1 protein (p.Glu1185Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 22711857, 34326862). ClinVar contains an entry for this variant (Variation ID: 89059). 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 with a negative predictive value of 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074581	SCV000600336	uncertain significance	not specified	2021-03-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165151	SCV000688440	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1185 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with ovarian cancer (PMID: 22711857). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765363	SCV000896628	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074581	SCV001437356	uncertain significance	not specified	2020-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3555G>T (p.Glu1185Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3555G>T has been reported in the literature in at least an individual with ovarian cancer (Alsop_2012). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165151	SCV003850215	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)	RCV000077551	SCV000109352	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-03-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000766573	SCV000591451	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1185Asp variant was identified in an individual with ovarian cancer in a study by Alsop (2012); however, control chromosomes were not evaluated in this study to assess variant frequencies in the general population. The variant is listed in the ClinVar database, with a classification of “uncertain” clinical significance by all three submitters (GeneDx, Sharing Clinical Reports Project, Ambry Genetics). The variant was not identified in other database searches (HGMD, GeneInsight – COGR, COSMIC, dbSNP, BIC, LOVD, Exome Variant Server Exome Sequencing Project, Exome Aggregation Consortium (ExAC)). One out of five in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a potential 3’ splice site just downstream of the variant; however, the variant is not located within a splicing consensus sequence and this information is not very predictive of pathogenicity. The p.Glu1185 residue is not conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 unknown significance.