Submissions for variant NM_000059.4(BRCA2):c.9235G>A (p.Val3079Ile) (rs55933907)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031803	SCV000244492	benign	Breast-ovarian cancer, familial 2	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 = 0.00002
Invitae	RCV000167789	SCV000073766	benign	Hereditary breast and ovarian cancer syndrome	2020-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000120369	SCV000210681	likely benign	not specified	2018-02-28	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.
Ambry Genetics	RCV000162558	SCV000212968	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.
Counsyl	RCV000031803	SCV000220450	likely benign	Breast-ovarian cancer, familial 2	2014-06-23	criteria provided, single submitter	literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120369	SCV000228108	likely benign	not specified	2016-01-25	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031803	SCV000267829	likely benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000167789	SCV000296862	likely benign	Hereditary breast and ovarian cancer syndrome	2015-11-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000768641	SCV000324843	likely benign	Breast and/or ovarian cancer	2015-09-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001283565	SCV000602840	likely benign	none provided	2019-10-15	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000162558	SCV000902658	benign	Hereditary cancer-predisposing syndrome	2015-10-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000031803	SCV001139250	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001114169	SCV001272014	uncertain significance	Fanconi anemia, complementation group D1	2018-01-23	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000031803	SCV001272015	likely benign	Breast-ovarian cancer, familial 2	2018-01-23	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Research and Development, ARUP Laboratories	RCV001642507	SCV001852836	benign	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031803	SCV000054411	likely benign	Breast-ovarian cancer, familial 2	2008-09-23	no assertion criteria provided	clinical testing
ITMI	RCV000120369	SCV000084521	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031803	SCV000147574	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656625	SCV000778724	likely benign	not provided	2017-05-19	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001354579	SCV001549227	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val3079Ile variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was not identified in 1362 control chromosomes from healthy individuals (Bodian, 2014, Borg 2010). The variant was also identified in dbSNP (ID: rs55933907) as With other allele, ClinVar (classified as benign by ENIGMA, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Counsyl, SCRP), Clinvitae (classified as benign by ClinVar, Invitae), LOVD 3.0 (5X predicted neutral), UMD-LSDB (11X likely neutral), BIC Database (22X with unknown significance), ARUP Laboratories ( not pathogenic or of no clinical significance ), databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 90 of 276464 chromosomes at a frequency of 0.000326 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Val3079 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 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. The variant is located with the BRCA2, oligonucleotide/oligosaccharide-binding 3 Nucleic acid-binding, OB-fold Breast cancer type 2 susceptibility protein functional domains increasing the likelihood that it may have clinical significance. In addition, multifactorial probability based model for classification of BRCA1 and BRCA2 variants of uncertain significance classified the variant as neutral with posterior probability of being deleterious 2.00√ó10-5 (Lindor 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.