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

dbSNP: rs276174831

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195304	SCV000072100	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	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.
Eurofins Ntd Llc (ga)	RCV000586739	SCV000225170	uncertain significance	not provided	2014-09-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000113115	SCV000488048	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120311	SCV000600532	benign	not specified	2021-07-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
Genetic Services Laboratory, University of Chicago	RCV000120311	SCV002067651	likely benign	not specified	2021-01-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149673	SCV003838820	likely benign	Breast and/or ovarian cancer	2021-10-12	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130805	SCV003847513	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
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, susceptibility to, 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.
Department of Medical and Surgical Sciences, University of Bologna	RCV000113115	SCV004228391	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)