Submissions for variant NM_000059.4(BRCA2):c.6220C>A (p.His2074Asn)

gnomAD frequency: 0.00264  dbSNP: rs34309943

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031609	SCV000244464	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 = 0.00000313
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167838	SCV000072887	benign	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000120334	SCV000167378	benign	not specified	2013-11-04	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.
Eurofins Ntd Llc (ga)	RCV000120334	SCV000202292	benign	not specified	2014-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162620	SCV000213053	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.
Illumina Laboratory Services, Illumina	RCV000167838	SCV000383732	likely benign	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000324816	SCV000383733	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167838	SCV000494336	benign	Hereditary breast ovarian cancer syndrome	2014-04-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120334	SCV000538461	benign	not specified	2021-05-17	criteria provided, single submitter	clinical testing	The p.His2074Asn variant in BRCA2 is classified as benign because it has been identified in 0.98% (243/24870) of African chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811231	SCV000602751	benign	not provided	2019-12-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162620	SCV000683760	benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031609	SCV000744483	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120334	SCV000805735	benign	not specified	2017-11-10	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167838	SCV002025795	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	RCV000735582	SCV002043311	likely benign	Breast and/or ovarian cancer	2020-11-04	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167838	SCV002515131	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162620	SCV002536212	benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167838	SCV005415591	benign	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing	The missense variant NM_000059.4(BRCA2):c.6220C>A (p.His2074Asn) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 38028 as of 2024-10-03). The variant is observed in one or more well-documented healthy adults. The p.His2074Asn variant is observed in 159/16,154 (0.9843%) alleles from individuals of gnomAD African background in gnomAD. The p.His2074Asn variant is observed in 14/5,008 (0.2796%) alleles from individuals of 1kG All background in 1kG, which is greater than expected for the disorder. There is a small physicochemical difference between histidine and asparagine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.His2074Asn missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The asparagine residue at codon 2074 of BRCA2 is present in David's myotis bat and 5 other mammalian species. The nucleotide c.6220 in BRCA2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign.
Sharing Clinical Reports Project (SCRP)	RCV000031609	SCV000054216	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-04-20	no assertion criteria provided	clinical testing
ITMI	RCV000120334	SCV000084486	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031609	SCV000146797	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120334	SCV000587832	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353448	SCV000592036	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.His2074Asn variant has been identified in one out of 190 control chromosomes (frequency 0.005), and also listed 39X in the BI(C database as a variant of unknown clinical significance (Wagner 1999). It is also listed in dbSNP database coming from a “clinical channel” (ID#: rs34309943) with a “global minor allele frequency of 0.001 (1000 genomes), therefore increasing the likelihood that this variant is benign. In the Exome Variant Server, this variant was also found in 45 times out of 12955 chromosomes (0 out of 8594 European, and 45 out of 4361 African alleles) further suggesting that the variant is benign. The p.His2074 residue is not conserved in mammals or in other species, and the computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In summary, based on above information this variant is classified as Benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735582	SCV000863720	benign	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120334	SCV001905910	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120334	SCV001958726	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120334	SCV002035718	benign	not specified		no assertion criteria provided	clinical testing