Submissions for variant NM_000059.4(BRCA2):c.476-9dup

dbSNP: rs276174849

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205599	SCV000259239	benign	Hereditary breast ovarian cancer syndrome	2022-10-12	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113650	SCV000267729	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001689639	SCV000565790	likely benign	not provided	2019-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580196	SCV000683651	likely benign	Hereditary cancer-predisposing syndrome	2015-02-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113650	SCV000743241	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478910	SCV000918854	likely benign	not specified	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.476-9dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. A functional study reported no impact on splicing, supporting these predictions (Houdayer_2012). The variant allele was found at a frequency of 3.2e-05 in 250658 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.476-9dupT has been reported in the literature in an individual affected with triple-negative breast cancer, but without strong evidence of causality (example, Wong-Brown_2015). Therefore, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In the UMD database a co-occurrence with another pathogenic variant has been reported (BRCA2 c.4936_4939delGAAA, p.Glu1646GlnfsX23) for this variant, providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 25682074). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=1), likely benign (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113650	SCV000146942	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000478910	SCV000587552	uncertain significance	not specified	2014-02-19	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689639	SCV001906437	likely benign	not provided		no assertion criteria provided	clinical testing