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

Total submissions: 8

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