ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5272A>G (p.Asn1758Asp) (rs80358750)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044624 SCV000072637 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 1758 of the BRCA2 protein (p.Asn1758Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs80358750, ExAC 0.002%). This variant has been observed in an individual with clinical features of a BRCA2-related disorder (Invitae). However, in that individual pathogenic allele[s] were also identified in BRCA2, which suggests that this c.5272A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51832). 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 aspartic acid 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.
Counsyl RCV000113413 SCV000488238 uncertain significance Breast-ovarian cancer, familial 2 2016-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000589423 SCV000567407 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5272A>G at the cDNA level, p.Asn1758Asp (N1758D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 5500A>G. This variant was observed in an individual with a personal and family history of breast cancer, whose tumor showed loss of heterozygosity (LOH) (Sorscher 2017). BRCA2 Asn1758Asp was not observed in large population cohorts (Lek 2016). This variant is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn1758Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562802 SCV000668581 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
Color RCV000562802 SCV000688925 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589423 SCV000694852 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5272A>G (p.Asn1758Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120396 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589423 SCV000887847 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113413 SCV000146586 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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