ClinVar Miner

Submissions for variant NM_007294.4(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 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164235 SCV000214856 likely benign Hereditary cancer-predisposing syndrome 2018-05-21 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000758803 SCV000329126 likely benign not provided 2020-12-14 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 2787G>A; Observed in an individual undergoing clinical BRCA1/2 testing (Trujillano 2015); This variant is associated with the following publications: (PMID: 12531920, 15235020, 15385441, 25556971, 31131967, 33087888)
Counsyl RCV000111911 SCV000488866 uncertain significance Breast-ovarian cancer, familial 1 2016-07-07 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 Health, Inc RCV000164235 SCV000903225 likely benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000407250 SCV000918717 likely benign not specified 2021-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2668G>A (p.Gly890Arg) results in a non-conservative amino acid change 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 an individual affected with papillary serous carcinoma of the peritoneum with non-informative BRCA1 LOH, a p53 tumor alteration (p.Trp49X) in tumor and no LOH of p53 (Schorge_2000). It has also been reported in an individual with Hereditary Breast and Ovarian Cancer (Trujillano_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database and at our laboratory (BRCA1 c.81-2del (IVS2-2delA)), providing supporting evidence for a benign role. 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. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; likely benign, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation and have re-classified this variant since its previous evaluation at our laboratory. Based on the emerging consensus among peers and all the evidence outlined above, the variant was re-classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111911 SCV000144503 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353659 SCV000591402 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Gly890Arg variant was identified in 1 of 420 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Trujillano 2015). The variant was also identified in dbSNP (ID: rs80357200) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Counsyl, Invitae, and BIC), Cosmic (1x in bone tissue), LOVD 3.0 (3x), and BIC Database (2x as unknown significance). The variant was not identified in UMD-LSDB, ARUP Laboratories, or Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gly890 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence; however, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing, suggesting that this variant may lead to aberrant splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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