ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.175C>G (p.Pro59Ala) (rs56091799)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081846 SCV000071888 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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: 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)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Health, Inc 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 2018-04-10 criteria provided, single submitter clinical testing
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 2 2009-10-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077263 SCV000146300 uncertain significance Breast-ovarian cancer, familial 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.

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