Submissions for variant NM_000465.4(BARD1):c.1904-5G>A

gnomAD frequency: 0.00003  dbSNP: rs376639978

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165063	SCV000215764	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-02	criteria provided, single submitter	clinical testing	The c.1904-5G>A intronic variant results from a G to A substitution 5 nucleotides upstream from coding exon 10 in the BARD1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635980	SCV000757410	likely benign	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165063	SCV000908560	likely benign	Hereditary cancer-predisposing syndrome	2017-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251377	SCV001426951	uncertain significance	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1904-5G>A 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 4e-06 in 251174 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1904-5G>A in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001711443	SCV001939297	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165063	SCV002529558	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000635980	SCV005407106	benign	Familial cancer of breast	2024-07-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].