ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2698A>G (p.Asn900Asp) (rs55736268)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130836 SCV000185734 likely benign Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000113078 SCV000146090 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000130836 SCV000903070 likely benign Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing
Counsyl RCV000113078 SCV000488497 uncertain significance Breast-ovarian cancer, familial 2 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000587512 SCV000567000 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2698A>G at the cDNA level, p.Asn900Asp (N900D) 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 2926A>G. This variant has been reported in individuals with breast cancer and one individual with pediatric-onset leukemia (Lee 2008, Zhang 2015, Parry 2017). BRCA2 Asn900Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Asn900Asp is not located in a known functional domain. 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 Asn900Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587512 SCV000694619 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2698A>G (p.Asn900Asp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/120568 control chromosomes at a frequency of 0.0000415, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant was reported in one BrC pt with no evidence to support the causative correlation of this variant with disease (Lee_2008). The variant was found in a patient in an internal sample who also carries a disease causing BRCA1 variant, c.2722G>T (p.Glu908X classified as pathogenic by LCA) suggesting a possibly benign impact. In addition, multiple clinical labs (via ClinVar) and database (BIC, BRCA Share) classified this variant as likely benign/VUS. Considering the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance until additional information becomes available.
Invitae RCV000044039 SCV000072052 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 900 of the BRCA2 protein (p.Asn900Asp). 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 (rs55736268, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer and acute lymphoblastic leukemia (PMID: 18284688, 26580448). ClinVar contains an entry for this variant (Variation ID: 51328). 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 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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