Submissions for variant NM_000059.4(BRCA2):c.5744C>T (p.Thr1915Met)

gnomAD frequency: 0.01834  dbSNP: rs4987117

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113476	SCV000245035	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02375 (European), derived from 1000 genomes (2012-04-30).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119140	SCV000153855	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113476	SCV000154063	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000120330	SCV000167375	benign	not specified	2013-09-16	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	RCV000128885	SCV000172742	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113476	SCV000195992	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120330	SCV000202291	benign	not specified	2015-04-09	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000119140	SCV000257612	benign	Hereditary breast ovarian cancer syndrome	2015-03-25	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000128885	SCV000267019	likely benign	Hereditary cancer-predisposing syndrome	2015-12-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120330	SCV000268810	benign	not specified	2015-06-29	criteria provided, single submitter	clinical testing	p.Thr1915Met in exon 11 of BRCA2: This variant is not expected to have clinical significance because it has been identified in 2.7% (1814/66580) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs4987117) and due to a lack of conservation across species, including >20 mammals which have a methionine (Met) at this position.
PreventionGenetics, part of Exact Sciences	RCV000120330	SCV000301765	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113476	SCV000383725	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000412748	SCV000492496	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000119140	SCV000494334	benign	Hereditary breast ovarian cancer syndrome	2014-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128885	SCV000537356	benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000467184	SCV000541024	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120330	SCV000586963	benign	not specified	2017-04-19	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000120330	SCV000588103	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034450	SCV000602777	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113476	SCV000743312	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	RCV000113476	SCV000744476	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109791	SCV001267161	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120330	SCV001469440	benign	not specified	2020-06-15	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034450	SCV002010351	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000119140	SCV002025784	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000119140	SCV002515125	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000128885	SCV002536169	benign	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120330	SCV002550354	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113476	SCV004016826	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113476	SCV004846640	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034450	SCV005236060	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034450	SCV000043217	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120330	SCV000084482	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113476	SCV000146687	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-17	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000113476	SCV000187736	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000113476	SCV000189310	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120330	SCV000591995	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1915Met variant was identified in 264 of 11658 proband chromosomes (frequency: 0.02) from individuals or families with breast and ovarian cancer (Borg 2010, D'Argenio 2015, Garre 2015, Schenkel 2016, Jalkh 2012, Serrano-Fernandez 2009, Meyer 2012, Cherbal 2012). The variant was also identified in the following databases: dbSNP (ID: rs4987117) as "With other allele", ClinVar (20X benign including review by expert panel ENIGMA, 3x likely benign, 2x uncertain significance), Clinvitae, GeneInsight-COGR (5x benign), Cosmic (3x, confirmed somatic, carcinoma of the large intestine and soft tissue), LOVD 3.0 (108x, predicted neutral), and the BIC Database (16x, not pathogenic). In UMD (41x, neutral biological significance) the variant was identified with co-occurring pathogenic variants: BRCA1 c.5137delG (p.Val1713X) and c.5266dup (p.Gln1756ProfsX74), BRCA2 c.3009_3010delCA (p.His1003GlnfsX5), c.5073dup (p.Trp1692MetfsX3), c.6405_6409delCTTAA (p.Asn2135LysfsX3), and c.7805G>C (p.Arg2602Thr), increasing the likelihood that the p.Thr1915Met variant does not have clinical significance. The variant was also identified by our laboratory in one individual with breast cancer. The variant was not identified in MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4962 of 276776 chromosomes (61 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 125 of 24016 chromosomes (freq: 0.005), Other in 123 of 6456 chromosomes (freq: 0.02), Latino in 304 of 34410 chromosomes (freq: 0.01), European in 3746 of 126392 chromosomes (freq: 0.03), Ashkenazi Jewish in 161 of 10142 chromosomes (freq: 0.02), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 229 of 25748 chromosomes (freq: 0.009), and South Asian in 272 of 30752 chromosomes (freq: 0.009). The p.Thr1915 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113476	SCV000733272	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034450	SCV000778691	benign	not provided	2016-12-28	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128885	SCV000787937	benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034450	SCV001799903	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120330	SCV001905831	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120330	SCV001959303	benign	not specified		no assertion criteria provided	clinical testing