ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000223167 SCV000276669 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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.
Color RCV000223167 SCV000683745 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160188 SCV000694921 likely benign not specified 2019-08-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5969A>C (p.Asp1990Ala) results in a non-conservative amino acid change located in the seventh BRCA2 repeat (IPR002093) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250616 control chromosomes (gnomAD), predominantly in East Asians, where it was reported in Korean subpopulation with a frequency of 0.002357. This frequency is about 3 fold higher than the expected maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075), suggesting a benign role for the variant. The variant, c.5969A>C, has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Han_2006, Seong_2009, Jang_2012, Hirotsu_2015, Nakamura_2013, Choi_2016, Kim_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another BRCA pathogenic variant (variant not specified, Nakamura_2013) has also been reported for this variant, which further supports its benign role. Two recent case-control association studies, involving breast cancer patients and controls of Korean (Park_2017) and Japanese ancestry (Momozawa 2018), found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of these studies classified this variant as likely benign/benign, respectively. In addition, in a study involving Korean breast cancer patients, multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology) and predicted this variant to be likely benign (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submissions (evaluation after 2014) classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589650 SCV000887858 uncertain significance not provided 2019-06-06 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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