Submissions for variant NM_000059.4(BRCA2):c.9924C>T (p.Tyr3308=)

gnomAD frequency: 0.00035  dbSNP: rs4987049

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112823	SCV000578003	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0011 (African), derived from ExAC (2014-12-17).
Invitae	RCV000195310	SCV000073928	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000045915	SCV000167425	benign	not specified	2014-03-14	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.
Ambry Genetics	RCV000163121	SCV000213633	likely benign	Hereditary cancer-predisposing syndrome	2014-06-19	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.
Counsyl	RCV000112823	SCV000487906	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045915	SCV000602826	benign	not specified	2016-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163121	SCV000684101	benign	Hereditary cancer-predisposing syndrome	2015-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590428	SCV000695282	likely benign	not provided	2016-12-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9924C>T (p.Tyr3308Tyr) variant causes a synonymous change involving a non-conserved nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing and no alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121266 (1/12127), predominantly in the African cohort, 10/10372 (1/1037), which does exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Therefore, suggesting that the variant is likely a benign polymorphism found in population(s) of African origin. The variant of interest has been reported in affected individual(s) via publications although with limited additional information (ie, cosegregation and co-occurrence data). However, a functional study found the variant to not differ from control cells (WT) in terms of sensitivity to MMC and etoposide, and RAD51 focus formation. In addition, multiple clinical diagnostic laboratories cite the variant as "benign." Therefore, the variant of interest has been classified as "Likely Benign."
Mendelics	RCV000112823	SCV001139278	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112895	SCV001270608	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	RCV000112823	SCV001270609	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195310	SCV002025885	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000045915	SCV002066865	likely benign	not specified	2021-05-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163121	SCV002532073	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590428	SCV004133004	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492373	SCV004240381	likely benign	Breast and/or ovarian cancer	2022-08-08	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112823	SCV000145731	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-11-30	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590428	SCV000778726	likely benign	not provided	2018-02-01	no assertion criteria provided	clinical testing