Submissions for variant NM_007294.4(BRCA1):c.2481A>C (p.Glu827Asp)

dbSNP: rs397508970

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216311	SCV000275030	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590050	SCV000698960	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2481A>C (p.Glu827Asp) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 4/121702 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in BrC pts as well as in normal controls in literatures. In addition, one clinical diagnostic laboratory via ClinVar classified this variant as likely benign and another lab via ClinVar classified this variant as VUS, without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000216311	SCV000909343	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 827 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 reported in a number of breast cancer case-controls studies in which this variant was detected in both affected and unaffected individuals. In a breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005182) and in a breast cancer case-control study in the South Korean population, this variant was detected in at least two affected individuals and two unaffected controls (PMID: 16949048, 17100994). This variant also has been reported in Japanese case-control studies on breast, pancreatic and prostate cancer, in which this variant was detected in one unaffected individual and was absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 1/250944 chromosomes 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.
Invitae	RCV001345360	SCV001539471	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-17	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 827 of the BRCA1 protein (p.Glu827Asp). This variant is present in population databases (rs397508970, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 17100994, 27383479, 31825140, 31907386). ClinVar contains an entry for this variant (Variation ID: 54580). 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	RCV000590050	SCV002046144	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250944 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 28692638 (2017), 27383479 (2016), 17100994 (2006), and 16949048 (2006)) and in healthy unaffected controls (PMIDs: 33471991 (2021), 32467295 (2020), and 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV001818226	SCV002067610	uncertain significance	not specified	2018-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000590050	SCV002504067	likely benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216311	SCV003847635	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)	RCV000077520	SCV000109321	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-03-25	no assertion criteria provided	clinical testing