ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5969A>C (p.Asp1990Ala) (rs148618542)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223167 SCV000276669 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000223167 SCV000683745 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000589650 SCV000210532 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5969A>C at the cDNA level, p.Asp1990Ala (D1990A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant, also published as BRCA2 6197A>C, has been reported in several individuals of Asian decent with a history of breast and/or ovarian cancer (Han 2006, Kim 2006, Seong 2009, Jang 2012, Hirotsu 2015, Nakamura 2015, Park 2016, Arai 2017, Hwang 2017, Park 2017). BRCA2 Asp1990Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the BRC7 domain and the region known to interact with RAD51 (Cole 2011, Roy 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Asp1990Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589650 SCV000694921 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5969A>C (p.Asp1990Ala) variant involves the alteration of a conserved nucleotide within the BRCA2 repeats region. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been confirmed via any in vitro/vivo functional studies at the time of classification. This variant was found in 6/121436 control chromosomes, predominantly observed in the East Asian subpopulation in ExAC at a frequency of 0.000578 (5/8650). This variant has been reported in the literature in at least two East Asian individuals affected with breast or ovarian cancer, without strong evidence for causality (no co-occurrence or co-segregation data provided). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance as well as a publication using multifactorial posterior probability and ACMG guidelines. Taken together, because of the lack of clinical information and the absence of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000460454 SCV000549696 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 1990 of the BRCA2 protein (p.Asp1990Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs148618542, ExAC 0.06%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16949048, 17100994, 19656164, 22217648, 24249303, 25802882, 29215753). ClinVar contains an entry for this variant (Variation ID: 91431). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). However, a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a low probability of being pathogenic (PMID: 27124784) 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160188 SCV000600672 uncertain significance not specified 2017-01-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589650 SCV000887858 uncertain significance not provided 2018-01-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076948 SCV000108745 uncertain significance Breast-ovarian cancer, familial 2 2011-12-16 no assertion criteria provided clinical testing

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