Submissions for variant NM_000059.4(BRCA2):c.8830A>T (p.Ile2944Phe) (rs4987047)

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083150	SCV000245217	benign	Breast-ovarian cancer, familial 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03455 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000045638	SCV000073651	benign	Hereditary breast and ovarian cancer syndrome	2020-12-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000083150	SCV000154075	benign	Breast-ovarian cancer, familial 2	2014-02-20	criteria provided, single submitter	literature only
GeneDx	RCV000120365	SCV000167414	benign	not specified	2013-09-17	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	RCV000131023	SCV000185951	benign	Hereditary cancer-predisposing syndrome	2014-06-16	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Michigan Medical Genetics Laboratories,University of Michigan	RCV000083150	SCV000196018	benign	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000083150	SCV000223760	benign	Breast-ovarian cancer, familial 2	2014-10-30	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120365	SCV000227872	benign	not specified	2014-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120365	SCV000301781	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000083150	SCV000383792	likely benign	Breast-ovarian cancer, familial 2	2018-01-29	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.
Illumina Clinical Services Laboratory,Illumina	RCV000317148	SCV000383793	likely benign	Fanconi anemia, complementation group D1	2018-01-29	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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413753	SCV000492483	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045638	SCV000494365	benign	Hereditary breast and ovarian cancer syndrome	2014-01-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000120365	SCV000538464	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: Ben by expert panel
Baylor Genetics	RCV000463955	SCV000541026	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001283529	SCV000602819	benign	none provided	2020-09-01	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131023	SCV000684000	benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083150	SCV000744550	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034467	SCV000043233	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120365	SCV000084517	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083150	SCV000115224	benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083150	SCV000147469	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000120365	SCV000592232	benign	not specified		no assertion criteria provided	clinical testing	The p.Ile2944Phe variant has been previously reported in the literature (Johnson 2007, Wagner 1999, Fackenthal 2005, Kim 2005). It has been previously identified in 6 out of 2146 proband chromosomes (frequency 0.003) in individuals with Breast Cancer, and in 3 out of 5110 control chromosomes (frequency 0.001). The Exome Variant Server has listed this variant in 1 out of 8599 genotype counts in a European American population, and 181 out 4225 genotype counts (frequency: 0.043) in an African American population, consistent with the observation that this variant was seen primarily in individuals of African decent in the literature above, and increasing the likelihood this is a common or benign polymorphism. This variant is listed in the BIC database under 115 entries as a variant with unknown clinical importance. It is also listed in the dbSNP database (ID#: rs4987047) with a minor allele frequency of 0.008 (1000 genomes) and up to 15% in some populations. The p.Ile2944 residue is conserved in the mammals and lower species examined, except in Opposum and Zebrafish where a Leucine (Leu) was present at this position, and increasing the likelihood an alteration to this residue may not have functional significance. In the UMD database, this variant has been identified in 1 out of 4 individuals with breast or ovarian cancers, where a second pathogenic BRCA2 mutation was also detected. In addition, this variant was previously identified by our laboratory in one individual who had a second pathogenic variant in the BRCA1 gene, increasing the likelihood the p.Ile2944Phe variant is benign. Computational analyses (AlignGVGD, PolyPhen2, SIFT, BLOSUM) provide inconsistent predictions regarding the impact to the protein; however, this information is not predictive enough to assume pathogenicity. However, functional studies including protein structure prediction, detection of full-length protein, no homologous recombination, no effect on splicing, and sensitivity to DNA damaging reagents, predict this variant to be "non-pathogenic" (Biswas 2012). Finally, Myriad reports this variant as a polymorphism (personal communication). In summary, 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 Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083150	SCV000733325	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034467	SCV000778720	benign	not provided	2017-10-11	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131023	SCV000787956	benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120365	SCV001798936	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000120365	SCV001906453	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120365	SCV001953738	benign	not specified		no assertion criteria provided	clinical testing