ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1550A>G (p.Asn517Ser) (rs80358439)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129057 SCV000183757 likely benign Hereditary cancer-predisposing syndrome 2016-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000031326 SCV000145886 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000129057 SCV000911038 likely benign Hereditary cancer-predisposing syndrome 2017-05-22 criteria provided, single submitter clinical testing
Counsyl RCV000031326 SCV000220903 likely benign Breast-ovarian cancer, familial 2 2014-11-21 criteria provided, single submitter literature only
GeneDx RCV000586299 SCV000210272 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1550A>G at the cDNA level, p.Asn517Ser (N517S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 1778A>G. This variant was observed in at least two families with a history of breast and/or ovarian cancer (Lu 2012, Quiles 2016), as well as in an individual with glioma (Lu 2015). BRCA2 Asn517Ser was predicted by Lindor et al. (2012) to be likely not pathogenic (IARC Class 2) based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious mutations. BRCA2 Asn517Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn517Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586299 SCV000694544 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: Variant summary: The BRCA2 c.1550A>G (p.Asn517Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/120276 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Despite this, the variant could still be a rare polymorphism. The variant was predicted to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Lindor_2012) and using a model based on tumor pathology and genetics including receptor status, tumor grade, loss of heterozygosity, and co-occurrence with deleterious mutations (Spearman_2008). The variant was reported to have no effect on splicing via patient RNA (Quiles_2016), however other deleterious effects cannot be ruled out. While one clinical laboratory classifies the variant as likely benign, four other classify as uncertain significance. One reputable database reports the variant as likely not pathogenic or of little clinical significance. Taken together, this variant has currently been classified as a VUS until additional evidence becomes available.
Invitae RCV000043826 SCV000071839 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 517 of the BRCA2 protein (p.Asn517Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs80358439, ExAC 0.002%). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22476429, 25556971, 26780556). ClinVar contains an entry for this variant (Variation ID: 37745). Based on a multifactorial likelihood algorithm using tumor pathology, clinical history, family studies, and co-occurrence data with deleterious mutations, this variant has been determined to have a low probability of being pathogenic (PMID: 21990134, 18824701). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000043826 SCV000838760 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031326 SCV000053931 uncertain significance Breast-ovarian cancer, familial 2 2013-01-08 no assertion criteria provided clinical testing

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