ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2083G>A (p.Asp695Asn) (rs28897681)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130220 SCV000185059 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing The p.D695N variant (also known as c.2083G>A<span style="background-color:initial">), located in coding exon 9 of the BRCA1<span style="background-color:initial"> gene, results from a G to A substitution at nucleotide position 2083. The aspartic acid at codon 695 is replaced by asparagine, an amino acid with highly similar properties. <span style="background-color:initial">This variant was reported in one hereditary breast ovarian cancer family from South Africa, however it segregated with disease in only two of three affected sisters and ethnically matched controls were not available (Greenman J et al. Genes Chromosomes Cancer. 1998 Mar;21(3):244-9). In an additional study, this alteration was reported as neutral based on several functional assays assessing the effect of p.D695N on BRCA1<span style="background-color:initial">-selectable<span style="background-color:initial"> conditional knockout mouse embryonic stem cells (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000111765 SCV000487950 uncertain significance Breast-ovarian cancer, familial 1 2015-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000440541 SCV000520968 likely benign not specified 2017-09-18 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.
Color Health, Inc RCV000130220 SCV000906721 benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985379 SCV001133512 likely benign not provided 2018-10-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000440541 SCV001362867 likely benign not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2083G>A (p.Asp695Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2083G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Greenman 1998) and colorectal carcinoma (Wei_2016). Greenman_1998 reports a family of three affected sisters, which one of the affected sisters did not carry the variant of interest, therefore, suggesting lack of cosegregation with disease. Two functional studies found the variant to not affect HDR activity (Lu_2015) and can rescue proliferation (Bouwman_2013). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as uncertain significance, twice as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV001324951 SCV001515922 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 695 of the BRCA1 protein (p.Asp695Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs28897681, ExAC 0.04%). This variant has been reported in a family affected with breast and/or ovarian cancer; the variant was present in two affected siblings and was absent from the third affected sibling (PMID: 9523200). This variant has also been reported in the Leiden Open-source Variation Database, in two individuals affected with breast cancer (PMID: 21520333). In one of those individuals a pathogenic allele was also identified in BRCA1, however, it is not clear whether these are germline or somatic alterations. ClinVar contains an entry for this variant (Variation ID: 54455). Experimental studies have shown that this missense change does not affect BRCA1 homology-directed repair activity in vitro (PMID: 26689913). BRCA1 protein containing this missense change restored cisplatin sensitivity to BRCA1-null mouse embryonic stem cells (PMID: 23867111). 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111765 SCV000144295 uncertain significance Breast-ovarian cancer, familial 1 1999-04-06 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677807 SCV000803966 uncertain significance Breast neoplasm 2017-09-05 no assertion criteria provided clinical testing

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