Submissions for variant NM_000465.4(BARD1):c.2275C>T (p.Pro759Ser)

dbSNP: rs1318628468

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569063	SCV000668233	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	clinical testing	The p.P759S variant (also known as c.2275C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2275. The proline at codon 759 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001294895	SCV001483793	uncertain significance	Familial cancer of breast	2023-06-09	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 482803). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 759 of the BARD1 protein (p.Pro759Ser).
Fulgent Genetics, Fulgent Genetics	RCV001294895	SCV002793576	uncertain significance	Familial cancer of breast	2021-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV003332202	SCV004040221	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17550235)
Baylor Genetics	RCV001294895	SCV004217188	uncertain significance	Familial cancer of breast	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569063	SCV004362614	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 759 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. In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 3/53458 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BARD1_000050). This variant has been identified in 1/251256 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.