Submissions for variant NM_000465.4(BARD1):c.1217G>A (p.Arg406Gln)

gnomAD frequency: 0.00002  dbSNP: rs587780014

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115609	SCV000149518	uncertain significance	not provided	2013-11-18	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.1217G>A at the cDNA level, p.Arg406Gln (R406Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has previously been reported as a somatic change in one endometrial tumor according to the Catalogue of Somatic Mutations in Cancer. BARD1 Arg406Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that only accepts changes to Glutamic Acid through mammals, but is not conserved below mammals, throughout evolution. This variant is not located in a known functional domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the BARD1 gene, remain unclear.
Ambry Genetics	RCV000222471	SCV000275338	likely benign	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000226218	SCV000284901	uncertain significance	Familial cancer of breast	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the BARD1 protein (p.Arg406Gln). This variant is present in population databases (rs587780014, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with colon cancer (PMID: 31371347). ClinVar contains an entry for this variant (Variation ID: 127713). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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	RCV000222471	SCV000911257	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 406 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that the variant protein is functional for homology-directed DNA repair in a cell-based assay (PMID: 26350354). Another study has reported normal BARD1-BRCA1 colocalization and RAD51 foci formation but impaired apoptosis in carrier-derived lymphoblastoid cells (PMID: 31371347). This variant has been reported in individuals affected with colon cancer (PMID: 31371347). This variant has been identified in 17/282356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cancer Genetics Service, National Cancer Centre Singapore	RCV000855729	SCV000920889	uncertain significance	Carcinoma of colon	2019-05-01	no assertion criteria provided	clinical testing