ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2926_2927delinsAT (p.Ser976Ile) (rs276174831)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195304 SCV000072100 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130805 SCV000185701 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV000120311 SCV000210582 benign not specified 2015-09-24 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586739 SCV000225170 uncertain significance not provided 2014-09-08 criteria provided, single submitter clinical testing
Counsyl RCV000113115 SCV000488048 likely benign Breast-ovarian cancer, familial 2 2015-12-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120311 SCV000600532 benign not specified 2017-06-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130805 SCV000683512 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586739 SCV000694650 benign not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.2926_2927delinsAT variant involves the alteration of two nucleotides resulting in an amino acid change from Ser to Ile. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.073%, predominantly observed in the African subpopulation at a frequency of 0.85%. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%) by 11-fold, suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in patients and controls in the literature and has been classified by multiple reputable clinical labs as "benign". Additionally, the variant was found to co-occur with pathogenic variants from several databases: BRCA1 c.3817C>T, p.Gln1273X (UMD); BRCA2 c.9026_9030delATCAT, p.Tyr3009_His3010?fs (BIC); BRCA1 c.815_824dupAGCCATGTGG, p.Thr276Alafs (BIC). Taken together, this variant has been classified as a benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120311 SCV001157043 likely benign not specified 2019-05-08 criteria provided, single submitter clinical testing
ITMI RCV000120311 SCV000084463 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000113115 SCV000146141 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353790 SCV000591836 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser976Ile variant was identified in 2 of 3116 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer (Lee_2008_18284688, Weitzel_2005_16030099). The variant was also identified in the following databases: dbSNP (ID: rs276174831) as “With other allele” , ClinVar (as benign by BIC, Invitae, Quest Diagnostics, Sinai Health System, LabCorp, CHEO, GeneDx, and Ambry Genetics, as likely benign by Counsyl and Color Genomics, and as uncertain significance by EGL Diagnostics), Clinvitae (with conflicting interpretations of pathogenicity), COGR (as benign by COGR consensus), LOVD 3.0 (13x), UMD-LSDB (11 x classified as neutral and co-occurring with a pathogenic BRCA1 variant p.Gln1273X), BIC Database (26 x in BIC with no classification). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in the Exome Aggregation Consortium (August 8th 2016), and the Genome Aggregation Database (Feb 27, 2017) listed under two different dbSNP identification numbers: rs11571656; rs144862123; in both cases it was identified in 167 of approximately 23980 African population chromosomes (frequency: 0.0069) and was also observed in Latino in 9 of 34204 chromosomes, increasing the likelihood that this may be a low frequency allele without clinical significance. This variant is an in-frame deletion resulting in the removal of a serine (Ser) residue at codon 976; the impact of this alteration on BRCA2 protein function is not known. Although the p.Ser976 residue is not conserved in mammals, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Ser976Ile variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. One in silico study yielded inconclusive risk predictions for this variant (Lee_2008). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our labortory's criteria to be classified as benign.

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