Submissions for variant NM_000059.4(BRCA2):c.4599A>C (p.Lys1533Asn)

gnomAD frequency: 0.00001  dbSNP: rs80358694

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044452	SCV000072465	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129285	SCV000184046	likely benign	Hereditary cancer-predisposing syndrome	2018-08-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000212237	SCV000210608	likely benign	not specified	2018-02-08	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.
Counsyl	RCV000077330	SCV000488129	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-06	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413529	SCV000492494	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281727	SCV000600596	likely benign	not provided	2020-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129285	SCV000903090	benign	Hereditary cancer-predisposing syndrome	2016-11-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109714	SCV001267077	uncertain significance	Fanconi anemia complementation group D1	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000077330	SCV001267078	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212237	SCV001983674	benign	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4599A>C (p.Lys1533Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250444 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4599A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.1547_1547delT, p.Phe516Serfs, BIC database; BRCA2 1775delT, Choi_2006; BRCA2 c.9382C>T, p.Arg3128X, internal database), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=5, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001281727	SCV002506244	likely benign	not provided	2022-01-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129285	SCV002533885	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149681	SCV003838825	likely benign	Breast and/or ovarian cancer	2021-09-14	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129285	SCV003850644	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000077330	SCV004845706	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077330	SCV000109127	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077330	SCV000146456	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353885	SCV000591913	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Lys1533Asn variant was identified in 4 of 2316 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was present in 1 of 638 control chromosomes (frequency: 0.02) from healthy individuals (Haffty 2009, Ho Choi 2004, Silva 2014, Suter 2004). The variant was also identified in dbSNP (ID: rs80358694) as “With other allele”, in ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Invitae, COGR, SCRP; as uncertain significance by Counsyl, BIC and two clinical laboratories), Clinvitae, GeneInsight-COGR, Cosmic, and BIC Database (unknown clinical importance). The variant was not identified in LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang University database. The variant was identified in control databases in 24 of 276676 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was specifically observed in the East Asian population in 24 of 18864 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Lys1533 residue is not conserved in mammals and 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.