ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5225A>T (p.Asn1742Ile) (rs756463217)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509611 SCV000608026 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000509611 SCV000683689 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000216156 SCV000279392 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5225A>T at the cDNA level, p.Asn1742Ile (N1742I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAC>ATC). Using alternate nomenclature, this variant would be defined as BRCA2 5453A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1742Ile was observed at an allele frequency of 0.02% (1/6604) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asn1742Ile occurs at a position that is not conserved and is located within the RAD51 and POLH binding domains (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 Asn1742Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000325274 SCV000383710 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000382610 SCV000383711 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780045 SCV000917062 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5225A>T (p.Asn1742Ile) 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 allele was found at a frequency of 2.2e-05 in 275430 control chromosomes. 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.5225A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six 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.
Invitae RCV000325274 SCV000549643 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 1742 of the BRCA2 protein (p.Asn1742Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs756463217, ExAC 0.02%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000216156 SCV000805719 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing

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