ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1181A>C (p.Glu394Ala) (rs56016241)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165113 SCV000215823 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077252 SCV000145825 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000165113 SCV000910939 likely benign Hereditary cancer-predisposing syndrome 2016-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000077252 SCV000488146 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000200974 SCV000210264 likely benign not specified 2017-08-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000589311 SCV000694517 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1181A>C (p.Glu394Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 3/5 in silico tools predict a damaging outcome for this variant, however no functional studies confirming impact of the variant on the protein function have been reported at the time of evaluation. The variant of interest has been identified in a large, broad control datasets of ExAC and gnomAD at a frequency of 0.000008 and 0.00002438 (1/120802 chrs and 6/246060 chrs tested, respectively). In gnomAD, the variant was identified exclusively in individuals of European ancestry (0.00005376; 6/111608 chrs tested). Although the observed frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), the variant may represent a rare ethnic-specific functional polymorphism. The variant of interest has been reported in multiple HBOC individuals via publications, including a record of co-occurrence of the variant with a known pathogenic allele, BRCA2 c.8168A>G, suggesting a benign outcome for the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS/Likely Benign. Taken together, this variant is classified as a VUS-Possibly Benign.
Invitae RCV000043752 SCV000071765 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 394 of the BRCA2 protein (p.Glu394Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs56016241, ExAC 0.001%). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 19619314, 19818148, 21120943), and is listed in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was identified in BRCA2, which suggests that the c.1181A>C variant was not the primary cause of disease in this individual. In the literature, this variant is also known as 1409A>C. ClinVar contains an entry for this variant (Variation ID: 51077). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000043752 SCV000838752 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200974 SCV000600472 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077252 SCV000109049 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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