Submissions for variant NM_000059.4(BRCA2):c.7057G>C (p.Gly2353Arg)

gnomAD frequency: 0.00006  dbSNP: rs80358935

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113701	SCV001161529	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	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 = 0.000782
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203630	SCV000073146	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130876	SCV000185780	likely benign	Hereditary cancer-predisposing syndrome	2018-08-20	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	RCV000590450	SCV000210643	likely benign	not provided	2020-08-31	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 29988080, 28678401, 22476429, 22678057, 10923033, 28283652, 28301460, 28263838, 21305653, 18403564, 22711857, 15026808, 20104584, 21952622, 21520273, 21671020, 21990134, 20127978, 24323938, 24728327)
Illumina Laboratory Services, Illumina	RCV000294899	SCV000383758	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000113701	SCV000383759	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120356	SCV000538489	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 3 labs classify as LB/Ben, 2 as VUS; ExAC: 5/66708 European chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000130876	SCV000683848	likely benign	Hereditary cancer-predisposing syndrome	2016-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590450	SCV000695033	likely benign	not provided	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7057G>C (p.Gly2353Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 8/122392 control chromosomes at a frequency of 0.0000654, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was found in HBOC spectrum patients however, without strong evidence for pathogenicity. In fact, the variant was observed in several patients to co-occur with (potentially) pathogenic BRCA1 and BRCA2 variants such as BRCA1 c.3193_3194insG (p.Asp1065?fs); BRCA2 c.4478_4481delAAAG (p.Glu1493_Ser1494?fs); BRCA2 c.476-2A>G; BRCA1 c.IVS5+1G>A (c.212+1G>A) BRCA1 c.3612delA (p.Ala1206ProfsX4), BRCA1 c.2346dupT indicating neutrality. Furthermore, Lindor_HM_2012 reviewed a multifactorial probability based model and calculated, odds in favor of causality was 0.03 and posterior probability of being deleterious 6.12104 and classified the variant as IARC Class I (Neutral) variant. Additionally, Alsop_2012 reports LOH of the variant within a breast tumor. Moreover, several clinical diagnostic laboratories classify variant as Benign/Likely benign via ClinVar. Considering all evidence, the variant was classified as Likely Benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735599	SCV002043430	likely benign	Breast and/or ovarian cancer	2021-03-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590450	SCV002047042	likely benign	not provided	2023-05-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120356	SCV002068369	uncertain significance	not specified	2018-03-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130876	SCV002531833	likely benign	Hereditary cancer-predisposing syndrome	2021-01-29	criteria provided, single submitter	curation
ITMI	RCV000120356	SCV000084508	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113701	SCV000147013	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113701	SCV000189314	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-25	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000113701	SCV000189910	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590450	SCV000592096	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Gly2353Arg variant was identified in 6 of 11570 proband chromosomes (frequency: 0.001) from individuals or families with (hereditary) breast and ovarian cancers and prostate cancer (Alsop 2012, Baila 2011, Borg 2010, Claes 2004, Kote-Jarai 2011, Morgan 2010). In a functional assay that evaluated the effect of the transient overexpression of the p.Gly2353Arg variant on spontaneous homologous recombination (HR) in a HeLa cell line, the variant increased HR as much as a pathogenic variant G2748D, which led the authors to classify it as possibly pathogenic (Baila 2011). However Lindor et al (2012) found the variant to be neutral based on a posterior probability model which combines segregation data, co-occurrence with pathogenic mutations, personal and family history of cancer and histopathology to determine a variant’s pathogenicity, suggesting a limited specificity of the recombination assay. Guidugli et al. 2014 also report the p.Gly2353Arg variant as “not pathogenic” citing that the Baila study does not measure a known BRCA2 function but rather an error prone repair mechanism such as single strand annealing in the absence of functional BRCA2 and therefore question the application of their assay to measure a BRCA2 variant’s function. The variant was identified in dbSNP (ID: rs80358935) with “Other” allele, Clinvitae database (with conflicting classifications), the ClinVar database (with conflicting interpretations of pathogenicity: classified as benign by Invitae, Pathway Genomics and Sharing Clinical Reports Project (derived from Myriad reports), as likely benign by Ambry Genetics, Illumina, and GeneDx, and as uncertain significance by BIC), GeneInsight COGR database (classifications uncertain significance, benign and unclassified “by 3 clinical laboratories), the BIC database (19x with unknown clinical importance, classification pending), the Fanconi Anemia Mutation Database-LOVD (1x as “probably affects function/not classified”) and UMD (9x with a ”unclassified variant” classification, and co-occurring with 2 pathogenic BRCA1 mutations (c.212+1G>A and c.3612delA, p.Ala1206ProfsX4) increasing the likelihood that the p.Gly2353Arg variant does not have clinical significance. This variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles, (frequency: 0.00012) and in the Exome Aggregation Consortium database (August 8, 2016) in 7 of 121030 chromosomes (freq. 00006) and in the Genome Aggregation Consortium (October 3, 2017) in the following populations: Other in 1 of 5472 chromosomes (freq. 0002), Latino in 1 of 33564 chromosomes (freq. 0.00003), and European (Non-Finnish) in 9 of 111462 chromosomes (freq. 0.00008), African in 1 of 15288 chromosomes (freq. 0.00007), but was not seen in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Myriad classifies this as a polymorphism (personal communication). The variant was also identified by our laboratory in 3 individuals with breast cancer. The p.Gly2353 residue is not conserved in mammals and 3 out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735599	SCV000863737	uncertain significance	Breast and/or ovarian cancer	2012-05-10	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120356	SCV001906235	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590450	SCV001931710	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120356	SCV001951261	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590450	SCV001971548	likely benign	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113701	SCV004228435	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BS3(Strong)+BP1(Strong)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)