ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5341G>A (p.Asp1781Asn) (rs183478654)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132288 SCV000187373 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000589648 SCV000278859 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5341G>A at the cDNA level, p.Asp1781Asn (D1781N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 5569G>A. This variant has been observed in at least one individual with breast cancer (Dean 2015). BRCA2 Asp1781Asn was not observed at a significant allele frequency in 1000 Genomes. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asp1781Asn occurs at a position that is not conserved and is located in the POLH binding domain (Buisson 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asp1781Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000409214 SCV000489111 uncertain significance Breast-ovarian cancer, familial 2 2016-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589648 SCV000694861 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5341G>A (p.Asp1781Asn) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 2/120702 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). A publication cites the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data)(Dean_BRCA_GigaScience_2015). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, due to the limited available information (ie, lack of clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS).
Invitae RCV000637785 SCV000759264 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1781 of the BRCA2 protein (p.Asp1781Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs183478654, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 26543556). ClinVar contains an entry for this variant (Variation ID: 142848). 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.

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