Submissions for variant NM_000465.4(BARD1):c.465A>G (p.Arg155=)

gnomAD frequency: 0.00001  dbSNP: rs730881413

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212115	SCV000209835	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000159807	SCV000215638	likely benign	Hereditary cancer-predisposing syndrome	2014-07-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199429	SCV000254582	uncertain significance	Familial cancer of breast	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 155 of the BARD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BARD1 protein. This variant is present in population databases (rs730881413, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182038). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000159807	SCV000911094	likely benign	Hereditary cancer-predisposing syndrome	2016-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000199429	SCV001296633	uncertain significance	Familial cancer of breast	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001543125	SCV001761644	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-07-22	criteria provided, single submitter	clinical testing	The BARD1 c.465A>G (p.Arg155=) synonymous change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/2-215646133-T-C). Algorithms that predict the impact of sequence changes on splicing indicate that this change may create or activate a cryptic donor splice site, but RNA studies indicate no splicing effect (internal data). This variant is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with HBOC. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting.
Sema4, Sema4	RCV000159807	SCV002529617	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-05	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212115	SCV004222401	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000008 (2/250902 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BARD1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000199429	SCV005405369	benign	Familial cancer of breast	2024-07-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact 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].