Submissions for variant NM_000059.4(BRCA2):c.175C>G (p.Pro59Ala)

gnomAD frequency: 0.00108  dbSNP: rs56091799

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081846	SCV000071888	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131721	SCV000186761	benign	Hereditary cancer-predisposing syndrome	2014-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000724406	SCV000210659	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29668487, 10923033, 24728327, 28873162, 21952622, 12491487)
Eurofins Ntd Llc (ga)	RCV000724406	SCV000228763	uncertain significance	not provided	2014-11-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120380	SCV000602790	likely benign	not specified	2016-10-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131721	SCV000683442	likely benign	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724406	SCV000887757	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001081846	SCV002026114	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120380	SCV002069415	likely benign	not specified	2021-12-01	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001081846	SCV002515240	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131721	SCV002533254	likely benign	Hereditary cancer-predisposing syndrome	2021-03-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120380	SCV002550240	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492346	SCV004240294	likely benign	Breast and/or ovarian cancer	2022-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537188	SCV004743321	likely benign	BRCA2-related disorder	2020-11-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000120380	SCV000084532	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077263	SCV000109060	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-10-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077263	SCV000146300	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358626	SCV001554417	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Pro59Ala variant was identified in the literature. The variant was also identified in dbSNP (ID: rs56091799) as “With Uncertain significance, other allele”, the Clinvitae and ClinVar databases (classified as benign by Invitae, Ambry Genetics; classified as likely benign by GeneDx, SCRP; classified as uncertain significance by CHEO, Emory Genetics and BIC), the BIC database (10x with unknown clinical importance), and UMD (25x with as an unclassified variant). In UMD the variant was identified in two patients, each with a separate pathogenic variant (BRCA1: c.5541C>A, p.Cys1847X and BRCA2: c.5641_5644delAAAT, p.Lys1881GlnfsX27), increasing the likelihood that the p.Pro59Ala variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the NHLBI GO Exome Sequencing Project in 13 of 4406 African American alleles (freq. 0.003), the genome Aggregation Database (beta, October 19th 2016) in 87 of 282602 chromosomes (freq. 0.0003), the Exome Aggregation Consortium database (August 8th 2016) in 28 of 121204 chromosomes (freq. 0.0002) in the following populations: African in 28 of 10306 chromosomes (freq. 0.002), but was not seen in Asian, European, Finnish, Latino and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was not identified in Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR database. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.