Submissions for variant NM_000465.4(BARD1):c.2153A>G (p.Asn718Ser)

gnomAD frequency: 0.00001  dbSNP: rs773166130

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483694	SCV000566224	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.2153A>G at the cDNA level, p.Asn718Ser (N718S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Asn718Ser was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BARD1 Asn718Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located within the BRCT2 domain (Fox 2008, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BARD1 Asn718Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000541644	SCV000633013	uncertain significance	Familial cancer of breast	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 718 of the BARD1 protein (p.Asn718Ser). This variant is present in population databases (rs773166130, gnomAD 0.006%). 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: 418856). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001184243	SCV001350187	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-29	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 718 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251376 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.
Ambry Genetics	RCV001184243	SCV002727013	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-11	criteria provided, single submitter	clinical testing	The p.N718S variant (also known as c.2153A>G), located in coding exon 11 of the BARD1 gene, results from an A to G substitution at nucleotide position 2153. The asparagine at codon 718 is replaced by serine, an amino acid with highly similar properties. In one study, this variant was not detected in 60,466 breast cancer cases but was seen in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.