ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7057G>C (p.Gly2353Arg) (rs80358935)

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Total submissions: 19
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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 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
Invitae RCV000203630 SCV000073146 benign Hereditary breast and ovarian cancer syndrome 2020-12-02 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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000113701 SCV000383759 likely benign Breast-ovarian cancer, familial 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, Partners HealthCare 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 Health, Inc 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.
Research and Development, ARUP Laboratories RCV001646615 SCV001854910 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 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 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113701 SCV000189314 benign Breast-ovarian cancer, familial 2 2011-02-25 no assertion criteria provided clinical testing
Pathway Genomics RCV000113701 SCV000189910 benign Breast-ovarian cancer, familial 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
Human Genetics - Radboudumc,Radboudumc RCV000120356 SCV001951261 benign not specified no assertion criteria provided clinical testing

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