Submissions for variant NM_000059.4(BRCA2):c.8007A>G (p.Arg2669=)

gnomAD frequency: 0.00002  dbSNP: rs143999963

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231287	SCV000283329	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565818	SCV000665951	likely benign	Hereditary cancer-predisposing syndrome	2023-07-11	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590364	SCV000695119	likely benign	not specified	2020-10-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000662966	SCV000785944	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565818	SCV000903268	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the BRCA2 protein. A minigene splicing assay suggests that this variant caused a partial splicing defect and resulted in exon 18 skipping in some RNA transcripts (PMID: 28339459, 31191615). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001711340	SCV001945430	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28339459)
Sema4, Sema4	RCV000565818	SCV002531902	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001711340	SCV004220583	uncertain significance	not provided	2023-01-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250812 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, a mini-gene splicing assay showed this variant causes exon 18 skipping in approximately 15% of the transcripts (PMID: 28339459 (2017)). Additional analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRCA2 mRNA splicing . This variant also co-occurred with pathogenic variants in the BRCA2 gene in two individuals in our internal patient population, suggesting it may not be the primary cause of disease. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000662966	SCV004845587	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the BRCA2 protein. A minigene splicing assay suggests that this variant caused a partial splicing defect and resulted in exon 18 skipping in some RNA transcripts (PMID: 28339459, 31191615). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000590364	SCV005090055	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535144	SCV004728104	likely benign	BRCA2-related disorder	2023-08-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).