ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2620A>C (p.Asn874His) (rs1064795862)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479303 SCV000572065 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2620A>C at the cDNA level, p.Asn874His (N874H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). Using alternate nomenclature, this variant has been previously published as BRCA1 2739A>C in at least one breast and ovarian cancer family (Anczukow 2008). A mini-gene assay demonstrated that BRCA1 Asn874His did not have an effect on splicing (Anczukow 2008). BRCA1 Asn874His 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. BRCA1 Asn874His occurs at a position that is not conserved and is located within the DNA and RAD51 binding domains (Chen 1998, Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Asn874His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545763 SCV000635859 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 874 of the BRCA1 protein (p.Asn874His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual from a breast and/or ovarian cancer family (PMID: 18273839). ClinVar contains an entry for this variant (Variation ID: 422565). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000570820 SCV000668454 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000570820 SCV000910431 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing

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