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

gnomAD frequency: 0.00018  dbSNP: rs55689095

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195380	SCV000073306	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-17	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	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.
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	likely benign	not provided	2022-03-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130819	SCV000683901	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549278	SCV000695096	likely benign	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7712A>G (p.Glu2571Gly) results in a non-conservative amino acid change located in the BRCA2 alpha helical domain superfamily of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 282778 control chromosomes, predominantly at a frequency of 0.00052 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.7712A>G has been reported in the literature, primarily in individuals of African or African American ancestry, affected with and undergoing testing for Hereditary Breast And Ovarian Cancer Syndrome (e.g. Haffty_2009, Francies_2015, Adedokun_2019, Ben Ayed-Guerfali_2021, Matta_2022, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.4986+6T>C), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (HDR) activity (e.g. Guidugli_2018, Hart_2019, Richardson_2021). HDR assays qualify as a standardized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31871109, 33726785, 28814288, 26577449, 29394989, 35264596, 19491284, 29884841, 19043619, 36329109, 33609447). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as eithe likely benign (n=4) or VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000195380	SCV000838860	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195380	SCV002025825	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000195380	SCV002515148	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000113807	SCV003806982	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, PP3 supporting, BS3 supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492366	SCV004240355	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113807	SCV000147165	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.