ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7457A>G (p.Asn2486Ser) (rs786203755)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167198 SCV000218035 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000167198 SCV000689048 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000255521 SCV000321482 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7457A>G at the cDNA level, p.Asn2486Ser (N2486S) 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 7685A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2486Ser was not observed in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn2486Ser is located in the DNA binding domain and within the FANCD2 and SHFM1 binding domains (Marston 1999, Yang 2002, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Asn2486Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637396 SCV000758852 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2486 of the BRCA2 protein (p.Asn2486Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 187467). 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 and their clinical significance is uncertain. 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.

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