Submissions for variant NM_000059.4(BRCA2):c.9839C>A (p.Pro3280His)

gnomAD frequency: 0.00001  dbSNP: rs80359246

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045904	SCV000073917	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130774	SCV000185667	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	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 a study of 1854 high-risk BR/OV cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71). Additionally, this alteration was identified in a cohort of unselected individuals pursuing BRCA1/2 testing in Turkey (Bisgin A et al. Breast J, 2019 09;25:1029-1033). This alteration was also detected in 1/1197 individuals diagnosed with breast cancer (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). 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, susceptibility to, 2	2015-12-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001703949	SCV000517197	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Variant behaved similar to wild-type in functional assays measuring RAD51 foci formation and sensitivity to mitomyocin C and etopocide (Hucl et al., 2008); Also known as 10067C>A; This variant is associated with the following publications: (PMID: 11929857, 25348012, 24323938, 27062684, 24817641, 29884841, 32377563, 18593900, 35402282, 31228304, 29684080, 34178674, 31853058)
Color Diagnostics, LLC DBA Color Health	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798244	SCV002041930	uncertain significance	Breast and/or ovarian cancer	2019-05-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130774	SCV002532064	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-04	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703949	SCV004220672	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 34178674 (2021), 31228304 (2019)). Published functional studies have reported that this variant does not have a deleterious effect on BRCA2 protein activity (PMID: 24323938 (2014), 18593900 (2008)). The frequency of this variant in the general population, 0.000016 (4/251302 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000077477	SCV000109275	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077477	SCV000145719	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077477	SCV004228305	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(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)
BRCAlab, Lund University	RCV000077477	SCV004243883	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing