Submissions for variant NM_000059.4(BRCA2):c.5785A>G (p.Ile1929Val)

gnomAD frequency: 0.00031  dbSNP: rs79538375

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031578	SCV000244461	benign	Breast-ovarian cancer, familial, susceptibility to, 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 = 0.00000521
Invitae	RCV000044755	SCV000072768	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000173974	SCV000108630	benign	not specified	2016-07-07	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	RCV000162909	SCV000213396	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: seen in unaffected individuals, 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	RCV000031578	SCV000220325	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-16	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000173974	SCV000225187	likely benign	not specified	2014-07-25	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031578	SCV000267788	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031578	SCV000383726	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-06	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000173974	SCV000538460	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: ExAC: 1% (85/8650) East Asian chromosomes
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000173974	SCV000586964	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173974	SCV000593720	likely benign	not specified	2016-07-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162909	SCV000683735	benign	Hereditary cancer-predisposing syndrome	2015-04-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031578	SCV000743313	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031578	SCV000744477	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000173974	SCV000885086	likely benign	not specified	2018-09-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110579	SCV001268031	likely benign	Fanconi anemia complementation group D1	2018-03-06	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237416	SCV002010350	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162909	SCV002536175	benign	Hereditary cancer-predisposing syndrome	2020-11-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173974	SCV002761169	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490438	SCV002797354	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031578	SCV004016873	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492314	SCV004240331	likely benign	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003237416	SCV005050221	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
Sharing Clinical Reports Project (SCRP)	RCV000031578	SCV000054184	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031578	SCV000146699	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Pathway Genomics	RCV000031578	SCV000187733	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000173974	SCV000592002	benign	not specified		no assertion criteria provided	clinical testing	The p.Ile1929Val variant has been reported in the literature in 21/19278 proband chromosomes from individuals with HBOC, sporadic breast cancer, as well as benign breast disease. It was also identified in 15/1406 control chromosomes (Borg_2010, Capanu_2011, Caux_Moncoutier_2010, Haffty_2009, Han_2006, Kim_2006, Lindor_2012, Seo_2004, Suter_2004, Thirthagiri_2008). This variant has been previously identified in our lab (n=3; benign classification) and in the UMD (n=1), LOVD (n=2), Exome Server as well as BOCs (ACMG category 5) databases. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs79538375) with a MAF score of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031578	SCV000733273	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000173974	SCV001905947	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173974	SCV001952363	benign	not specified		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV001762065	SCV002520810	likely benign	Familial cancer of breast		no assertion criteria provided	literature only