ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1259A>G (p.Asp420Gly) (rs730881442)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159846 SCV000209889 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1259A>G at the cDNA level, p.Asp420Gly (D420G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA1 1378A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Asp420Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Asp420Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204508 SCV000260519 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 420 of the BRCA1 protein (p.Asp420Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182076). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000214615 SCV000275439 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409308 SCV000488029 uncertain significance Breast-ovarian cancer, familial 1 2015-12-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515362 SCV000611443 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000214615 SCV000682943 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779906 SCV000916814 uncertain significance not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1259A>G (p.Asp420Gly) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245590 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1259A>G, has been reported in the literature in one individual with high risk of Hereditary Breast and Ovarian Cancer (Laitman_2011). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159846 SCV001133480 uncertain significance not provided 2019-04-13 criteria provided, single submitter clinical testing

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