ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2803G>C (p.Asp935His) (rs28897716)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113094 SCV001161612 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000816
Invitae RCV000586933 SCV000072075 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131164 SCV000186109 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000586933 SCV000278841 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2803G>C at the cDNA level, p.Asp935His (D935H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant, also known as BRCA2 3031G>C using alternate nomenclature, has been observed in several individuals with a personal or family history of breast cancer, one individual with pancreatic cancer, and one individual with prostate cancer (Edwards 2003, Vogel 2007, Haffty 2009, Caux-Moncoutier 2011, Becker 2012, Hu 2015). BRCA2 Asp935His was observed at an allele frequency of 0.009% (6/66390) in individuals of European (non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp935His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Asp935His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113094 SCV000487999 uncertain significance Breast-ovarian cancer, familial 2 2015-12-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586933 SCV000694630 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2803G>C (p.Asp935His) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 6/120746 control chromosomes at a frequency of 0.0000497, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It was observed in unaffected individual with a family history of HBOC and several HBOC spectrum patients without strong evidence for pathogenicity. A metaphase-based radiation assay by Becker_Breast Cancer Res Treat_2012 demonstrated that the variant resembles a neutral character indicating a benign impact. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Furthermore, a different variant affecting the same codon (D935N) has been classified as Normal Variant by our laboratory. Considering all evidence, the variant is classified as a VUS-possibly benign until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586933 SCV000889010 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing
Color RCV000131164 SCV000902829 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000113094 SCV001139043 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002667 SCV001160655 uncertain significance not specified 2019-06-27 criteria provided, single submitter clinical testing The BRCA2 c.2803G>C; p.Asp935His variant (rs28897716), is reported in the literature in individuals with breast and/or ovarian cancer (Caux-Moncoutier 2011, Haffty 2009, Vogel 2007) and in individuals with prostate cancer (Edwards 2003). This variant is reported in ClinVar but with conflicting interpretations (Variation ID: 37801). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (16/250844 alleles) in the Genome Aggregation Database. The aspartate at codon 935 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this BRCA2 variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34. Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan; 72 (1):1-12. Haffty BG et al. Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and rish of secondary malignancies across diverse racial groups. Ann Oncol. 2009 Oct; 20(10):1653-9. Vogel KJ et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol. 2007 Oct 10; 25(29):4635-41.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113094 SCV000146114 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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