ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2669G>T (p.Gly890Val) (rs80356874)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031060 SCV000244327 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000408
Invitae RCV000225761 SCV000075930 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131935 SCV000186991 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000047917 SCV000209944 likely benign not specified 2017-07-07 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.
Counsyl RCV000031060 SCV000488506 benign Breast-ovarian cancer, familial 1 2016-04-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282802 SCV000602720 likely benign none provided 2019-09-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131935 SCV000902874 benign Hereditary cancer-predisposing syndrome 2016-10-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656633 SCV001133533 likely benign not provided 2019-03-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047917 SCV001361733 likely benign not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2669G>T (p.Gly890Val) 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 allele was found at a frequency of 2e-05 in 251020 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.2669G>T, has been reported in affected individuals via publications with no co-segregation information to rule in or rule out causation. In particular, the variant has been reported (Schorge_2001) in one family to be present in an unaffected individual. No details about the nature or extent of family member testing (i.e., co-segregation) were provided. Authors called this variant as a polymorphism. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007 and Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 (2x VUS, 4x likely benign, 3x benign). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031060 SCV000053655 uncertain significance Breast-ovarian cancer, familial 1 2008-11-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031060 SCV000144504 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353549 SCV000591403 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Gly890Val variant was identified in 2 of 9848 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer (Schorge 2001, van der Hout 2006). The variant was identified in dbSNP (rs80356874) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Sinai Health System, BIC and SCRP, likely benign by Ambry Genetics, GeneDx, ARUP and Mayo Clinic and benign by ENIGMA, Counsyl and Color) and LOVD 3.0 (observed 5x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 5 of 251,020 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 16,254 chromosomes (freq: 0.0001), European in 3 of 113,454 chromosomes (freq: 0.00003), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Gly890Val residue is not conserved in mammals and four out of five 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 and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000656633 SCV000778751 likely benign not provided 2017-09-12 no assertion criteria provided clinical testing

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