Submissions for variant NM_000059.4(BRCA2):c.9730G>A (p.Val3244Ile) (rs11571831)

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114158	SCV000245313	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 0.02642 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000167853	SCV000073906	benign	Hereditary breast and ovarian cancer syndrome	2020-12-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000114158	SCV000154086	benign	Breast-ovarian cancer, familial 2	2014-03-18	criteria provided, single submitter	literature only
Ambry Genetics	RCV000128917	SCV000172784	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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120377	SCV000202308	benign	not specified	2015-04-29	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000167853	SCV000257621	likely benign	Hereditary breast and ovarian cancer syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000114158	SCV000267832	benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000768643	SCV000324841	benign	Breast and/or ovarian cancer	2015-12-10	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000313558	SCV000383804	benign	Fanconi anemia, complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV000114158	SCV000383805	benign	Breast-ovarian cancer, familial 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167853	SCV000494347	benign	Hereditary breast and ovarian cancer syndrome	2014-04-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469360	SCV000541041	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency	RCV000120377	SCV000586992	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282539	SCV000602873	benign	none provided	2020-06-24	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000128917	SCV000684089	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114158	SCV000744793	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128917	SCV000747800	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120377	SCV000805801	benign	not specified	2017-04-13	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034473	SCV000043238	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120377	SCV000084529	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114158	SCV000147705	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	RCV001353392	SCV000592306	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val3244Ile variant was identified in the literature in 5/7922 proband chromosomes (frequency: 0.001) from individuals with breast cancer; however, no control chromosomes were tested to establish the frequency of the variant in the general population (Borg 2010, Caux-Moncoutier 2011; Haffty 2009). The variant was also identified in the BIC database (73X with unknown clinical importance) and in UMD (28X as an unclassified variant) where it was listed to co-occur with a pathogenic mutation in BRCA1 (c.2551G>T (p.Glu851X)), increasing the likelihood that this variant may not have clinical importance. The p.Val3244 residue is not conserved in mammals, and the variant amino acid Isoleucine (Ile) is present in macaque at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not predict any effect on the protein function; however, this information is not predictive enough to rule out pathogenicity. The variant is listed in dbSNP as coming from a "clinical source" (ID#: rs11571831) with a minor allele frequency of 0.006 (1000 Genomes). It was also identified in the NHLBI Exome Sequencing Project with a frequency of 0.025 in African American alleles, and in several HapMap populations including HapMap-YRI (frequency: 0.032), HapMap-JPT (frequency: 0.03) and HapMap-CEU (frequency: 0.033), increasing the likelihood that this is a low frequency benign polymorphism in certain populations of origin. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034473	SCV000778725	likely benign	not provided	2017-12-23	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000120377	SCV001906184	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120377	SCV001956446	benign	not specified		no assertion criteria provided	clinical testing