ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6225A>C (p.Lys2075Asn) (rs80358863)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130739 SCV000185630 likely benign Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Breast Cancer Information Core (BIC) (BRCA2) RCV000076957 SCV000146800 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000130739 SCV000683761 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000076957 SCV000785313 uncertain significance Breast-ovarian cancer, familial 2 2017-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000255403 SCV000321473 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6225A>C at the cDNA level, p.Lys2075Asn (K2075N) 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 6453A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2075Asn was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys2075Asn occurs at a position that is not conserved and is located within the BRC8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). 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 BRCA2 Lys2075Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000558324 SCV000635498 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 2075 of the BRCA2 protein (p.Lys2075Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs80358863, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91440). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Sharing Clinical Reports Project (SCRP) RCV000076957 SCV000108754 likely benign Breast-ovarian cancer, familial 2 2012-06-13 no assertion criteria provided clinical testing

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