Submissions for variant NM_000059.4(BRCA2):c.3302A>G (p.His1101Arg)

gnomAD frequency: 0.00001  dbSNP: rs398122761

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129726	SCV000184531	likely benign	Hereditary cancer-predisposing syndrome	2017-12-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000196747	SCV000254180	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1101 of the BRCA2 protein (p.His1101Arg). This variant is present in population databases (rs398122761, gnomAD 0.001%). This missense change has been observed in individual(s) with breast cancer, male breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 21520333, 27882536, 28767289, 30613976, 34326862). ClinVar contains an entry for this variant (Variation ID: 91796). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000077704	SCV000489189	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000657002	SCV000566035	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3530A>G; This variant is associated with the following publications: (PMID: 25583493, 31422574, 27882536, elebi2022[article], 30613976, 32659497, 29309945, Bahsi2020[case report], 28767289)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657002	SCV000600545	uncertain significance	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129726	SCV000910977	likely benign	Hereditary cancer-predisposing syndrome	2016-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483080	SCV000918842	uncertain significance	not specified	2017-10-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.3302A>G (p.His1101Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/225626 control chromosomes at a frequency of 0.00044%, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.075%). The variant was reported in one patient with Br/OC (Loizidou 2017), however no further information was provided on this case (i.e. no exact diagnosis, and co-occurrence or co-segregation data were included), thus limiting independent evaluation of causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000483080	SCV002550321	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129726	SCV003851841	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657002	SCV004565144	uncertain significance	not provided	2023-05-24	criteria provided, single submitter	clinical testing	The BRCA2 c.3302A>G; p.His1101Arg variant (rs398122761) is reported in the literature in individuals affected with breast, ovarian, and pancreatic cancer (Bahsi 2020, Loizidou 2017, Rizzolo 2019, Shindo 2017). This variant is also reported in ClinVar (Variation ID: 91796). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.231). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bahsi T et al. Spectrum of BRCA1/BRCA2 variants in 1419 Turkish breast and ovarian cancer patients: a single center study. Turkish Journal of Biochemistry. 2020;45(1): 83-90. Loizidou MA et al. BRCA1 and BRCA2 mutation testing in Cyprus; a population based study. Clin Genet. 2017 Apr;91(4):611-615. PMID: 27882536. Rizzolo P et al. Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer. 2019 Jul 15;145(2):390-400. PMID: 30613976. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289.
Sharing Clinical Reports Project (SCRP)	RCV000077704	SCV000109507	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-09	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077704	SCV004243602	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing