ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7712A>G (p.Glu2571Gly) (rs55689095)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195380 SCV000073306 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130819 SCV000185715 likely benign Hereditary cancer-predisposing syndrome 2019-11-20 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
GeneDx RCV000590609 SCV000210443 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7712A>G at the cDNA level, p.Glu2571Gly (E2571G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 7940A>G. BRCA2 Glu2571Gly has been observed in at least two women with pre-menopausal and/or triple negative breast cancer (Haffty 2009, Francies 2015). BRCA2 Glu2571Gly was observed at an allele frequency of 0.05% (13/24,030) in individuals of African ancestry in large population cohorts (Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2571Gly occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Glu2571Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590609 SCV000600766 uncertain significance not provided 2020-01-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130819 SCV000683901 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glycine at codon 2571 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, a functional study has shown that the variant protein has neutral impact on homology-directed DNA repair activity (PMID: 29394989, 29884841). This variant has been reported in individuals affected with breast cancer (PMID: 19491284, 26577449, 31871109, 32231682). This variant has also been identified in 15/282778 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 RCV000590609 SCV000695096 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7712A>G (p.Glu2571Gly) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/121342 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000482 (5/10382). The variant is also present in a control population dataset of gnomAD at a frequency of 0.00005 (15/277138 chrs), mainly in individuals of African origin: 0.00054 (13/24030 chrs). Although, these frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), the prevalence of the variant in African sub-cohorts suggests that the variant of interest may be an ethnic-specific functional polymorphism. The variant has been reported in affected individuals of African origin in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, including one report of co-occurrence with a pathogenic BRCA1 variant, suggesting the variant of interest is not the primary cause of disease in that patient. Taken together, this variant is classified as VUS-Possibly Benign.
Mendelics RCV000195380 SCV000838860 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113807 SCV000147165 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045293 SCV000592137 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Glu2571Gly variant was not identified in probands in the literature. The variant was identified in dbSNP (ID: rs55689095) “With Uncertain significance allele, LOVD, the ClinVar database (classified with uncertain significance by Ambry Genetics), the BIC database (3X with unknown clinical importance), and UMD (1X as a unclassified variant). The variant was identified by the Exome Variant Server project in 2 of 4406 African American alleles (frequency: 0.0005) and in the 1000 Genomes Project in 1 allele (frequency 0.0005), although this low number of observations and low frequency is not substantive enough to determine its relationship to disease. The p.Glu2571 residue is conserved across mammals, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu2571Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. An in silico study using a protein likelihood-ratio model predicted the variant to be neutral (Karchin 2012). 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 unknown significance.

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