Submissions for variant NM_000059.4(BRCA2):c.2960A>T (p.Asn987Ile)

gnomAD frequency: 0.00356  dbSNP: rs2227944

Total submissions: 23

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, 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 = 0.0000741
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167849	SCV000072108	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	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, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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: 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	RCV000077289	SCV000220278	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-29	criteria provided, single submitter	literature only
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000077289	SCV000383666	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome	2014-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656594	SCV000602854	benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162623	SCV000683516	benign	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120316	SCV000805680	benign	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120316	SCV002550316	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149674	SCV003838150	benign	Breast and/or ovarian cancer	2022-05-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077289	SCV004016870	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656594	SCV005236046	benign	not provided		criteria provided, single submitter	not provided
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, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077289	SCV000146150	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077289	SCV000189895	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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