ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2892A>T (p.Lys964Asn) (rs587778119)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120315 SCV000293735 uncertain significance not specified 2015-12-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2892A>T at the cDNA level, p.Lys964Asn (K964N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 3120A>T. This variant has been reported in one individual each from India and Pakistan with a personal and/or family history of breast and/or ovarian cancer (Soumittra 2009, Ahmad 2012). It was also reported in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. BRCA2 Lys964Asn 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Lys964Asn occurs at a position that is not conserved and is located in the region of interaction with NPM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys964Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238991 SCV000296521 uncertain significance Breast-ovarian cancer, familial 2 2016-05-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120315 SCV000591833 uncertain significance not specified 2014-10-23 criteria provided, single submitter clinical testing
Invitae RCV000557314 SCV000635253 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 964 of the BRCA2 protein (p.Lys964Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs587778119, ExAC 0.04%). This variant has been observed in individuals affected with breast and/or ovarian cancer PMID: 19656415, 28288110, 22486713, 28288110). ClinVar contains an entry for this variant (Variation ID: 133728). 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.
Color RCV000771211 SCV000903249 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120315 SCV000918892 uncertain significance not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2892A>T (p.Lys964Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant is found at a frequency of 4.9e-05 in the gnomAD database (11/243536 control chromosomes). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.2892A>T has been reported in the literature in affected individuals. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV000771211 SCV001177894 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing Insufficient evidence
ITMI RCV000120315 SCV000084467 not provided not specified 2013-09-19 no assertion provided reference population

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