ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2668G>A (p.Gly890Arg) (rs80357200)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047916 SCV000075929 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 890 of the BRCA1 protein (p.Gly890Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 25556971). This variant also has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.2668G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 54634). 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 arginine 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 RCV000164235 SCV000214856 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
GeneDx RCV000758803 SCV000329126 uncertain significance not provided 2016-09-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2668G>A at the cDNA level, p.Gly890Arg (G890R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). Using alternate nomenclature, this variant would be defined as BRCA1 2787G>A. BRCA1 Gly890Arg was identified in at least one individual with a personal and/or family history consistent with hereditary breast and ovarian cancer (Trujillano 2015). Studies of evolutionary conservation reached conflicting conclusions regarding the significance of this variant (Fleming 2003, Abkevich, 2004). BRCA1 Gly890Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly890Arg occurs at a position that is not conserved and is located in the DNA binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Gly890Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000111911 SCV000488866 uncertain significance Breast-ovarian cancer, familial 1 2016-07-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000407250 SCV000591402 uncertain significance not specified 2015-04-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758803 SCV000887652 uncertain significance not provided 2019-05-17 criteria provided, single submitter clinical testing
Color RCV000164235 SCV000903225 likely benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000407250 SCV000918717 uncertain significance not specified 2019-06-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2668G>A (p.Gly890Arg) results in a non-conservative amino acid change within the RAD51-binding domain (Fleming_2003 ) in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2668G>A has been reported in the literature in individuals affected with papillary serous carcinoma of the peritoneum or Hereditary Breast and Ovarian Cancer (Schorge_2000, Trujillano_2014). These reports do 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111911 SCV000144503 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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