ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4320A>C (p.Lys1440Asn) (rs769535925)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478901 SCV000566437 uncertain significance not provided 2015-04-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4320A>C at the cDNA level, p.Lys1440Asn (K1440N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 4548A>C. This variant was observed once in a series of Korean breast cancer patients suspected of having hereditary breast and/or ovarian cancer susceptibility (Seong 2009). BRCA2 Lys1440Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys1440Asn occurs at a position that is conserved in mammals and is located in the 3rd BRC repeat domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Lys1440Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000529148 SCV000635360 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1440 of the BRCA2 protein (p.Lys1440Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs769535925, ExAC 0.02%). This variant has been reported in an individual with breast cancer (PMID: 27124784), and in an individual with personal and/or family history of breast/ovarian or multi-organ cancer (PMID: 19656164). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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