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

gnomAD frequency: 0.00004  dbSNP: rs80356874

Total submissions: 15

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, susceptibility to, 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 ovarian cancer syndrome	2024-01-19	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656633	SCV000209944	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22753008, 16267036, 11606101, 16683254, 21990134, 17924331, 12531920, 15235020)
Counsyl	RCV000031060	SCV000488506	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656633	SCV000602720	likely benign	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2023-03-06	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). Eleven submitters (including an expert panel-ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000225761	SCV002025972	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131935	SCV002538146	likely benign	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031060	SCV000053655	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-11-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031060	SCV000144504	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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