Submissions for variant NM_000059.4(BRCA2):c.8530G>A (p.Glu2844Lys)

dbSNP: rs755783122

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215245	SCV000274059	likely benign	Hereditary cancer-predisposing syndrome	2021-10-01	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	RCV000232530	SCV000283346	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662587	SCV000383786	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000307069	SCV000383787	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000215245	SCV000683978	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2844 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in four individuals affected with breast and/or ovarian cancer (PMID: 29470806, 33552952) and in a breast cancer case-control meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008679). This variant has been identified in 14/251140 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.
Counsyl	RCV000662587	SCV000785213	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477718	SCV004220612	uncertain significance	not provided	2024-08-21	criteria provided, single submitter	clinical testing	The BRCA2 c.8530G>A (p.Glu2844Lys) variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 29470806 (2018), 32885271 (2021), 33552952 (2020), and 34101484 (2021), as well as in a reportedly healthy individual in a large scale breast cancer association study (PMID: 33471991 (2021)), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.00046 (14/30614 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000662587	SCV004846035	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2844 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in four individuals affected with breast and/or ovarian cancer (PMID: 29470806, 33552952) and in a breast cancer case-control meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008679). This variant has been identified in 14/251140 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503308	SCV000592206	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu2844Lys variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs755783122) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, Color, COGR and Illumina). The variant was also identified by our laboratory in 3 individuals with breast cancer. The variant was identified in control databases in 14 of 245874 chromosomes (1 homozygous) at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: and South Asian in 14 of 30780 chromosomes (freq: 0.0005), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Glu2844 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.