ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4695G>T (p.Lys1565Asn) (rs587782522)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131707 SCV000186745 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000200646 SCV000254185 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1565 of the BRCA2 protein (p.Lys1565Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142527). 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 asparagine 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.
GeneDx RCV000481655 SCV000566169 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4695G>T at the cDNA level, p.Lys1565Asn (K1565N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 4923G>T. While this variant has been identified in a gastrointestinal tumor, it has not, to our knowledge, been published in the literature as a germline variant (van der Heijden 2006). BRCA2 Lys1565Asn was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys1565Asn occurs at a position that is not conserved and is located within the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Lys1565Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781154 SCV000919026 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4695G>T (p.Lys1565Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 30954 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4695G>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481655 SCV001133809 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000239158 SCV000297528 uncertain significance Breast-ovarian cancer, familial 2 2011-01-19 no assertion criteria provided clinical testing

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