ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9839C>A (p.Pro3280His) (rs80359246)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045904 SCV000073917 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130774 SCV000185667 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing The p.P3280H variant (also known as c.9839C>A), located in coding exon 26 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9839. The proline at codon 3280 is replaced by histidine, an amino acid with similar properties. In an in vitro study, this variant was found to have a neutral phenotype in a panel of functional assays that used RAD51 focus formation and mitomycin C sensitivity to evaluate BRCA2 protein function (Hucl T et al. Cancer Res. 2008 Jul; 68(13):5023-30). This amino acid position is highly conserved on sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000077477 SCV000488003 uncertain significance Breast-ovarian cancer, familial 2 2015-12-16 criteria provided, single submitter clinical testing
GeneDx RCV001703949 SCV000517197 likely benign not provided 2021-03-23 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18593900, 11929857, 25348012, 24323938, 27062684, 24817641)
Color Health, Inc RCV000130774 SCV000911112 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000430520 SCV000917028 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9839C>A (p.Pro3280His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246074 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9839C>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Azzollini_2016), who was also indicated to carry another pathogenic variant, although the variant was not indicated. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. An in vitro study demonstrated the variant to behave similar to wild type BRCA2 in DNA damaging agent sensitivity and Rad51 foci formation assays indicating a possible neutral impact (Hucl_2008). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000077477 SCV000109275 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077477 SCV000145719 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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