Submissions for variant NM_007294.4(BRCA1):c.884A>G (p.Asp295Gly)

gnomAD frequency: 0.00008  dbSNP: rs772684048

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217932	SCV000277515	likely benign	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537146	SCV000636081	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 295 of the BRCA1 protein (p.Asp295Gly). This variant is present in population databases (rs772684048, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21156238, 31954625, 34218100). ClinVar contains an entry for this variant (Variation ID: 233188). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000217932	SCV000683373	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 295 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 one individual each affected with breast or ovarian cancer, as well as an unaffected control individual (PMID: 21156238, 26541979). This variant has been identified in 20/251246 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501807	SCV001360621	uncertain significance	not specified	2019-08-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.884A>G (p.Asp295Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00065 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-05 vs 0.001), allowing no conclusion about variant significance. c.884A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Manguoglu_2010, Hasmad_2016), but also in a healthy control subject (Manguoglu_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000537146	SCV002026009	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001689754	SCV002774115	likely benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000217932	SCV003847876	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).
All of Us Research Program, National Institutes of Health	RCV004804918	SCV004818401	uncertain significance	BRCA1-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 295 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer, an individual affected with ovarian cancer and one individual unaffected with cancer (PMID: 21156238, 26541979, 34218100), and this variant also has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005730). This variant has been identified in 20/251246 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.
GeneDx	RCV001689754	SCV005328125	uncertain significance	not provided	2024-03-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1003A>G; This variant is associated with the following publications: (PMID: 33471991, 34218100, 9582019, 9788437, 9926942, 15343273, 20215511, 26541979, 31954625, 21156238)
Fulgent Genetics, Fulgent Genetics	RCV005016602	SCV005647184	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-02-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353575	SCV000591306	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.884A>G variant was not identified in the literature. The variant was identified in dbSNP (ID: rs772684048) as “With Uncertain Significance allele”, Clinvitae database (as uncertain significance), and the ClinVar database (as uncertain significance, by Ambry Genetics). The variant was not found in the Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR database, the BIC database, and UMD. This variant was identified in the Exome Aggregation Consortium database (August 8th, 2016) in 8 of 121358 chromosomes (freq. 6.59X10-5) in the following populations: South Asian in 8 of 16504 chromosomes (freq. 0.00048), but was not seen in African, East Asian, Finnish, European (Non-Finnish), and Latino populations, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asp295 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689754	SCV001906225	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001689754	SCV001954611	likely benign	not provided		no assertion criteria provided	clinical testing