Submissions for variant NM_000059.3(BRCA2):c.517-4C>G (rs81002804)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083460	SCV000072603	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000212206	SCV000167325	benign	not specified	2014-04-07	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	RCV000131488	SCV000186476	likely benign	Hereditary cancer-predisposing syndrome	2018-06-27	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044590	SCV000296597	benign	not provided	2018-12-24	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000212206	SCV000694837	uncertain significance	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.517-4C>G 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251480 control chromosomes, predominantly at a frequency of 0.00037 within the African or African-American subpopulation in the gnomAD database. This frequency is lower than the expected maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075); therefore the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.517-4C>G variant has been reported in the literature in individuals affected with breast cancer (Pal_2015, Abulkhair_2018) and also in controls (Wagner_1999), but without strong evidence for or against causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (4x), benign (2x) or VUS (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000113731	SCV000785180	likely benign	Breast-ovarian cancer, familial 2	2017-05-22	criteria provided, single submitter	clinical testing
Color	RCV000131488	SCV000903207	likely benign	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000113731	SCV001138969	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000113731	SCV001269105	uncertain significance	Breast-ovarian cancer, familial 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.
Illumina Clinical Services Laboratory,Illumina	RCV001111541	SCV001269106	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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113731	SCV000147051	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113731	SCV000297535	benign	Breast-ovarian cancer, familial 2	2012-09-11	no assertion criteria provided	clinical testing