ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6434A>G (p.Asn2145Ser) (rs80358878)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044945 SCV000072958 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2145 of the BRCA2 protein (p.Asn2145Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs80358878, ExAC 0.002%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52094). 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 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
GeneDx RCV000758928 SCV000210388 uncertain significance not provided 2014-12-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6434A>G at the cDNA level, p.Asn2145Ser (N2145S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant, also known as c.6662A>G using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2145Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn2145Ser occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn2145Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165446 SCV000216176 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758928 SCV000887878 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing
Color RCV000165446 SCV000903524 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077374 SCV000109171 uncertain significance Breast-ovarian cancer, familial 2 2011-12-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077374 SCV000146850 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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