ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131164 SCV000186109 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113094 SCV000146114 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131164 SCV000902829 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Counsyl RCV000113094 SCV000487999 uncertain significance Breast-ovarian cancer, familial 2 2015-12-11 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.
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.
Invitae RCV000044062 SCV000072075 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 935 of the BRCA2 protein (p.Asp935His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs28897716, ExAC 0.009%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17925560, 19491284, 21120943), prostate cancer (PMID: 12474142), and pancreatic cancer (PMID: 26483394). This variant has also been observed in an unaffected individual from a family with hereditary breast and ovarian cancer (PMID: 22729890). This variant is also known as 3031G>C in the literature. ClinVar has an entry for this variant (Variation ID: 37801). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586933 SCV000889010 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing

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