ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2960A>T (p.Asn987Ile) (rs2227944)

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Total submissions: 20
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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) RCV000077289 SCV000244433 benign Breast-ovarian cancer, familial 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 = 0.0000741
Invitae RCV000167849 SCV000072108 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000120316 SCV000167350 benign not specified 2013-10-08 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077289 SCV000195972 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120316 SCV000202281 benign not specified 2014-02-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162623 SCV000213058 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.
Counsyl RCV000077289 SCV000220278 benign Breast-ovarian cancer, familial 2 2014-04-29 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000365242 SCV000383665 likely benign Fanconi anemia, complementation group D1 2018-02-02 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000077289 SCV000383666 likely benign Breast-ovarian cancer, familial 2 2018-02-02 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167849 SCV000494313 benign Hereditary breast and ovarian cancer syndrome 2014-03-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283409 SCV000602854 benign none provided 2020-08-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162623 SCV000683516 benign Hereditary cancer-predisposing syndrome 2015-09-30 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120316 SCV000805680 benign not specified 2016-11-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646121 SCV001854740 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
ITMI RCV000120316 SCV000084468 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077289 SCV000109086 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077289 SCV000146150 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000077289 SCV000189895 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353508 SCV000591840 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn987Ile variant was identified in 2/139220 proband chromosomes of individuals with breast cancer and/or HBOC and was present in in 2/148 control chromosomes from healthy individuals (Fackenthal 2005, Lee 2008, Rajasekaran 2008, Spearman 2008). The p.Asn987Ile variant has been previously observed in our laboratory. The variant was identified in dbSNP (ID: rs2227944) “With Benign allele”, Clinvitae database (classification benign by multiple submitters), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database (classified as not pathogenic/of no clinical importance), ARUP Laboratories BRCA Mutations Database (classification not pathogenic/no clinical importance), the ClinVar database (classification benign, reviewed by an expert panel, multiple submitters), GeneInsight COGR database (3X, classification likely benign, benign, and unclassified by clinical laboratories), the BIC database (41X with no clinical importance), and UMD (72X with a “neutral” classification, co-occurring with multiple pathogenic mutations in BRCA2: c.5213_5216delCTTA (p.Thr1738IlefsX2)/c.6405_6409delCTTAA (p.Asn2135LysfsX3)), and in BRCA1: c.4945_4947delinsTTTT (p.Arg1649SerfsX30)/ c.5038_5041dup (p.Thr1681AsnfsX3)/ c.4484G>A (p.Arg1495Lys), increasing the likelihood that the p.Asn987Ile variant does not have clinical significance. This variant was also identified in the 1000 Genomes Project in 10 of 5000 chromosomes (frequency: 0.002), HAPMAP-GLOBAL in 2 of 174 chromosomes (frequency: 0.0115), NHLBI GO Exome Sequencing Project in 1 of 8586 European American alleles (frequency: 0.00012) and in 47 of 4406 African American alleles (frequency: 0.01067); and in the Exome Aggregation Consortium database (March 14, 2016) in 105 of 120300 chromosomes (freq. 00087) in the following populations: African in 101 of 9930 chromosomes (freq. 0.01017), Latino in 3 of 11504 chromosomes (freq. 00026), European (Non-Finnish) in 1 of 66224 chromosomes (freq. 0.00002), but was not seen in East Asian, European (Finnish), Other, and South Asian populations. Myriad classifies this as a polymorphism (personal communication). The p.Asn987 residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; however, this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656594 SCV000778658 benign not provided 2018-02-28 no assertion criteria provided clinical testing

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