Submissions for variant NM_000465.4(BARD1):c.1808C>A (p.Thr603Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881421

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159819	SCV000209852	uncertain significance	not provided	2018-07-03	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.1808C>A at the cDNA level, p.Thr603Lys (T603K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BARD1 Thr603Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain (Fox 2008, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BARD1 Thr603Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474889	SCV000545636	uncertain significance	Familial cancer of breast	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 603 of the BARD1 protein (p.Thr603Lys). This variant is present in population databases (rs730881421, gnomAD 0.0009%). 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: 182050). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV000564659	SCV000660801	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The p.T603K variant (also known as c.1808C>A), located in coding exon 8 of the BARD1 gene, results from a C to A substitution at nucleotide position 1808. The threonine at codon 603 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564659	SCV000904047	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 603 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 1/251106 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229764	SCV002511512	uncertain significance	not specified	2022-04-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474889	SCV004214941	uncertain significance	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000474889	SCV005406730	likely benign	Familial cancer of breast	2024-07-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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].
GenomeConnect - Invitae Patient Insights Network	RCV000474889	SCV004228897	not provided	Familial cancer of breast		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-04-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.