ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2920G>A (p.Asp974Asn) (rs539613324)

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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 RCV000132411 SCV000187503 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000132411 SCV000903059 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000485759 SCV000591835 uncertain significance not specified 2014-02-27 criteria provided, single submitter clinical testing
GeneDx RCV000657012 SCV000566362 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2920G>A at the cDNA level, p.Asp974Asn (D974N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 3148G>A. This variant has been reported in a Chinese patient with breast and/or ovarian cancer, as well as in a cohort of healthy control subjects from Hong Kong (Kim 2016, Kwong 2016). BRCA2 Asp974Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Asp974Asn is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Asp974Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167943 SCV000218591 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 974 of the BRCA2 protein (p.Asp974Asn). 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 (rs539613324, ExAC 0.05%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142931). 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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