Submissions for variant NM_000059.4(BRCA2):c.5640T>G (p.Asn1880Lys)

gnomAD frequency: 0.00288  dbSNP: rs11571657

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077358	SCV001161664	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00909 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044703	SCV000072716	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001703946	SCV000167373	benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21520273, 25637381, 11241844, 27884173, 26332594, 24728327, 11950811, 12624724, 9971877, 20104584, 19491284, 16030099, 22034289, 18724707, 12491487, 27741520)
Ambry Genetics	RCV000129180	SCV000183915	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	RCV000077358	SCV000220345	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-23	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000120348	SCV000225180	benign	not specified	2014-12-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077358	SCV000267783	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000301382	SCV000383721	likely benign	Fanconi anemia complementation group D1	2018-10-25	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	RCV000077358	SCV000383722	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-25	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	RCV000044703	SCV000494332	benign	Hereditary breast ovarian cancer syndrome	2014-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120348	SCV000593717	benign	not specified	2018-07-20	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129180	SCV000679718	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129180	SCV000683720	benign	Hereditary cancer-predisposing syndrome	2016-05-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120348	SCV000805728	benign	not specified	2017-07-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703946	SCV000883470	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000077358	SCV001139120	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044703	SCV002026123	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735568	SCV002043203	likely benign	Breast and/or ovarian cancer	2020-03-27	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044703	SCV002515123	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129180	SCV002536156	benign	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120348	SCV002550350	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703946	SCV004132990	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120348	SCV004848030	benign	not specified	2022-01-28	criteria provided, single submitter	clinical testing	The p.Asn1880Lys variant in BRCA2 is classified as benign because it has been identified in 0.92% (229/24894, 2 homozygotes) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as benign on Jun 18, 2019 by the ClinGen-approved ENIGMA expert panel (Variation ID 51896). ACMG/AMP Criteria applied: BA1.
Breakthrough Genomics, Breakthrough Genomics	RCV001703946	SCV005236059	benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120348	SCV000084500	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077358	SCV000109155	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-08-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077358	SCV000146650	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148422	SCV000190121	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120348	SCV000587783	benign	not specified	2015-12-17	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077358	SCV000591981	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Asn1880Lys variant has been previously observed in 7/5248 (frequency: 0.001) proband chromosomes from individuals with a family history of breast and/or ovarian cancer (Borg 2010, Haffty 2009, Real 2002, Weitzel 2005). This individuals racial origin is reported to be of African American ancestry and of the individuals reported in the literature with the p.Asn1880Lys variant, 3 were reported of African American descent. In addition, in the Exome Variant Server this variant was not found in any of the 8,600 Caucasian control chromosomes, but was found in 41/4365 (frequency: 0.009) African American control chromosomes increasing the likelihood that this variant is a benign polymorphism in this population of origin. It should also be noted that this lab has sequenced the BRCA2 gene in a limited number of African American individuals such that the full spectrum of benign variation has not yet been defined for this population, and increasing the possibility that this may be a benign variant. Future analysis could reveal that the p.Asn1880Lys variant is common in this population and therefore unlikely to be of clinical significance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs11571657) with a global minor allele frequency (MAF) of 0.002 (1000 Genomes) further lending to a benign role for this variant. Finally, this residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, further leaning to a benign role for this variant. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in this individual, but based on the above information this variant is classified as benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735568	SCV000863706	pathogenic	Breast and/or ovarian cancer	2012-05-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077358	SCV004243677	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing