Submissions for variant NM_000059.4(BRCA2):c.5095G>A (p.Asp1699Asn)

gnomAD frequency: 0.00006  dbSNP: rs80358731

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081347	SCV000072565	benign	Hereditary breast ovarian cancer syndrome	2022-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130358	SCV000185209	likely benign	Hereditary cancer-predisposing syndrome	2019-03-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000590213	SCV000526371	likely benign	not provided	2020-05-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19912264, 22752604, 28692054, 26580448, 30555256, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590213	SCV000694827	benign	not provided	2016-03-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031527	SCV000786230	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130358	SCV000902797	likely benign	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001818199	SCV001133816	benign	not specified	2019-02-15	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001081347	SCV002026108	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818199	SCV002067567	likely benign	not specified	2018-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130358	SCV002533924	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818199	SCV002761164	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149598	SCV003838162	likely benign	Breast and/or ovarian cancer	2022-03-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031527	SCV000054132	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031527	SCV000146533	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-02-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590213	SCV000591939	likely benign	not provided		no assertion criteria provided	clinical testing	The p.Asp1699Asn variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), GeneInsight COGR, COSMIC, MutDB, ARUP laboratories or LOVD databases. The p.Asp1699Asn variant was identified in dbSNP (ID: rs80358731 “With other allele”, with a minor allele frequency of 0.0006 (3 of 5000 chromosomes in1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13th, 2015) in 64 of 118544 chromosomes (frequency: 0.0005399) or 62 of 15484 alleles from a population of South Asians with 1 homozygous, 2 of 884 alleles of other populations and was not found in European (Non-Finnish), East Asian, African, Latino, European (Finnish) and individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified by our laboratory in 2 individuals with ovarian and breast cancers. The ClinVar database had conflicting interpretations: classified as a likely benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), by Invitae and Ambry Genetics whereas BIC classified the variant as uncertain significance. The BRCA Share UMD database classified the variant as unknown. In-silico splicing predictors do not predict any difference in splicing. The p.Asp1699 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 amino acid Asparagine (Asn) is present in Cows, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as Likely Benign.