Submissions for variant NM_000059.4(BRCA2):c.8525G>A (p.Arg2842His)

gnomAD frequency: 0.00005  dbSNP: rs80359105

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077444	SCV000244486	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000259
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084291	SCV000073558	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000587725	SCV000210671	likely benign	not provided	2020-11-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 21990134, 24323938, 21218378, 19043619, 20167696, 28624499, 11304778, 26757417, 18284688, 14520696, 25348012, 16683254, 28324225, 18951446, 29394989, 30093976, 32444794, 29884841)
Ambry Genetics	RCV000163013	SCV000213501	benign	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Counsyl	RCV000077444	SCV000487766	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163013	SCV000537493	likely benign	Hereditary cancer-predisposing syndrome	2020-03-13	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000045545	SCV000588120	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045545	SCV000695163	benign	not specified	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8525G>A (p.Arg2842His) results in a non-conservative amino acid change located in the Tower domain (IPR015205) 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 6e-05 in 251110 control chromosomes, predominantly at a frequency of 0.00049 within the East Asian subpopulation in the gnomAD database. In addition, this variant was also reported in 3/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). The variant, c.8525G>A, has been reported in the literature in individuals breast cancer, however without strong evidence for causality (e.g. Martin_2001, Weber-Mangal_2003, Lee_2008, Ng_2016, Chan_2018) as well as in at least one individual with a positive family history of breast, ovarian, or pancreatic cancer (Carney_2010). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 10/60466 cases, but was also found in 11/53461 controls (Dorling_2021, reported through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2685_2686del, p.Pro897fs (LOVD database); BRCA1 c.2635G>T, p.E879X (Chan_2018)), providing supporting evidence for a benign role. Multiple publications reported experimental evidence evaluating an impact on protein function, and in general demonstrated similar activity to the wild-type, including homology-directed DNA repair (HDR) assays (e.g. Guidugli_2018, Ikegami_2020, Brnich_2021, Richardson_2021, Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 33964450, 21218378, 30093976, 29394989, 32444794, 19043619, 18284688, 11304778, 26757417, 14520696, 33609447, 33471991, 37922907). ClinVar contains an entry for this variant (Variation ID: 52611). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077444	SCV000743348	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077444	SCV000744541	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587725	SCV001961403	likely benign	not provided	2021-07-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587725	SCV002049588	likely benign	not provided	2021-05-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163013	SCV002531955	likely benign	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045545	SCV004243069	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077444	SCV000109242	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077444	SCV000147391	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077444	SCV000733318	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358481	SCV001554226	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2842His variant was identified in 5 of 3552 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Chao 2016, Lee 2008, Martin 2001, Ng 2016). The variant was also identified in dbSNP (ID: rs80359105 as With Uncertain significance, other allele), ClinVar (13x as benign or likely benign, reviewed by an expert panel), LOVD 3.0 (17x between benign and inconclusive), UMD-LSDB (1 x as likely neutral), and ARUP Laboratories (as not pathogenic). The variant was not identified in Cosmic, MutDB, BIC Database, or Zhejiang University Database. The variant was identified in control databases in 16 of 276812 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Latino in 1 of 34416 chromosomes (freq: 0.00003), European Non-Finnish in 6 of 126350 chromosomes (freq: 0.00005), and East Asian in 8 of 18852 chromosomes (freq: 0.0004); it was not observed in the “Other”, Ashkenazi Jewish, Finnish, and South Asian populations. One study showed homology-directed DNA repair activity by the p.Arg2842His variant (Guidugli 2018) and mathematical models predict that this variant is benign (Easton 2007, Lindor 2012). The p.Arg2842 residue is 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 reliably 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, the clinical significance of this variant cannot be determined with certainty at this time, although the information currently available suggests a benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000045545	SCV001906170	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000045545	SCV001953199	benign	not specified		no assertion criteria provided	clinical testing