ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7448G>A (p.Ser2483Asn) (rs80358967)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082083 SCV000073233 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129898 SCV000184716 benign Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
GeneDx RCV000586632 SCV000210649 likely benign not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19043619, 18824701, 22476429, 27741520, 29884841)
Counsyl RCV000083134 SCV000487957 uncertain significance Breast-ovarian cancer, familial 2 2015-12-10 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045220 SCV000588113 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129898 SCV000683873 likely benign Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045220 SCV000695068 likely benign not specified 2020-04-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7448G>A (p.Ser2483Asn) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7448G>A has been reported in the literature in individuals affected with breast cancer and also in individuals at risk of hereditary breast cancer (Spearman_2008, Carr_2011, Lu_2012, Fernandes_2016, Vendrell_2018) without strong evidence of causality. These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another likely pathogenic variant has been reported (BRCA2 c.7115C>G, p.Ser2372X) in the UMD database, providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Hart_2019). Nine other ClinVar Submitters (evaluation after 2014) cite the variant as benign (n=6) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586632 SCV001133897 likely benign not provided 2019-03-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586632 SCV001148990 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646656 SCV001854923 likely 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
Sharing Clinical Reports Project (SCRP) RCV000083134 SCV000115208 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083134 SCV000147091 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000083134 SCV000592111 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Ser2483Asn variant was identified in 1 of 698 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and identified in 4 family members (Fernandes 2016). The variant was also identified in dbSNP (ID: rs80358967) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx and three other submitters; as uncertain significance by four submitters), COGR, MutDB, LOVD 3.0 (6x), UMD-LSDB (4x as unclassified variant), and in BIC Database (4x with unknown significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.7115C>G, p.Ser2372X), increasing the likelihood that the p.Ser2483Asn variant does not have clinical significance. The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 5 of 246090 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111588 chromosomes (freq: 0.000045), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser2483 residue is not conserved in mammals and 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the p.Ser2483Asn variant was identified in the literature in two reports that use various prediction models to try to determine the clinical significance of this variant. Both reports imply that the variant is predicted neutral (Karchin 2008, Spearman 2008). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000586632 SCV000778709 likely benign not provided 2018-02-09 no assertion criteria provided clinical testing

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