ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4344T>G (p.Asn1448Lys) (rs1064793724)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481338 SCV000566867 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4344T>G at the cDNA level, p.Asn1448Lys (N1448K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 4572T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1448Lyswas not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn1448Lys occurs at a position that is not conserved and is located within the BRC3 domain, and the RAD51 and POLH binding domains (Cole 2011, Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn1448Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000539583 SCV000635361 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-11-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1448 of the BRCA2 protein (p.Asn1448Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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