ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5744C>T (p.Thr1915Met) (rs4987117)

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Total submissions: 35
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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 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).
Invitae RCV000119140 SCV000153855 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000113476 SCV000154063 benign Breast-ovarian cancer, familial 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: 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 2 2014-11-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 and 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, Partners HealthCare 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,PreventionGenetics RCV000120330 SCV000301765 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113476 SCV000383725 benign Breast-ovarian cancer, familial 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 and ovarian cancer syndrome 2014-01-15 criteria provided, single submitter clinical testing
Color Health, Inc 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 RCV001282431 SCV000602777 benign none provided 2020-08-31 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113476 SCV000743312 benign Breast-ovarian cancer, familial 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 2 2015-09-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
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 2 2010-12-17 no assertion criteria provided clinical testing
Pathway Genomics RCV000113476 SCV000187736 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000113476 SCV000189310 benign Breast-ovarian cancer, familial 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 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
Human Genetics - Radboudumc,Radboudumc RCV000120330 SCV001959303 benign not specified no assertion criteria provided clinical testing

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