ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7042A>C (p.Asn2348His) (rs55742659)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509958 SCV000608251 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000484747 SCV000572304 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7042A>C at the cDNA level, p.Asn2348His (N2348H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 7270A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2348His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2348His occurs at a position that is not conserved 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 evidence, it is unclear whether BRCA2 Asn2348His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637661 SCV000759130 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 2348 of the BRCA2 protein (p.Asn2348His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs55742659, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 422755). 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 histidine 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. 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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