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

gnomAD frequency: 0.00005  dbSNP: rs761863671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163727	SCV000214301	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-12	criteria provided, single submitter	clinical testing	The c.-4G>A variant is located in the 5' untranslated region (5’ UTR) of the BARD1 gene. This variant results from a G to A substitution 4 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588551	SCV000696775	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.-4G>A variant involves the alteration of a non-conserved nucleotide in the 5UTR region. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 18828 control chromosomes. In addition, another clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588551	SCV000887596	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with BARD1-related conditions in the published literature. The frequency of this variant in the general population, 0.000092 (7/76156 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000163727	SCV000910844	likely benign	Hereditary cancer-predisposing syndrome	2015-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000588551	SCV001945153	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895113	SCV004715432	likely benign	BARD1-related condition	2021-02-03	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356902	SCV001552185	uncertain significance	Familial cancer of breast		no assertion criteria provided	clinical testing	The BARD1 c.-4G>A variant was not identified in the literature nor was it identified in the COSMIC, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs761863671) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (1x classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 7 of 176022 chromosomes (no homozygotes) at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 7 of 73398 chromosomes (freq: 0.000095), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The c.-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.