Submissions for variant NM_000465.4(BARD1):c.632T>A (p.Leu211Ter)

dbSNP: rs762171436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657689	SCV000779438	likely pathogenic	not provided	2016-06-24	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.632T>A at the cDNA level and p.Leu211Ter (L211X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
GeneKor MSA	RCV000657689	SCV000821707	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Leucine to a premature translational stop signal at codon 211 of the BARD1 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in BARD1 are known to be pathogenic (PMID: 21344236, 22006311, 20077502). This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747).
Ambry Genetics	RCV001025144	SCV001187276	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-21	criteria provided, single submitter	clinical testing	The p.L211* variant (also known as c.632T>A), located in coding exon 4 of the BARD1 gene, results from a T to A substitution at nucleotide position 632. This changes the amino acid from a leucine to a stop codon within coding exon 4. This alteration has been identified in a patient affected with pancreatic ductal adenocarcinoma (PDAC) with a family history of four additional relatives affected with PDAC (Chaffee KG et al. Genet. Med., 2018 01;20:119-127). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001387044	SCV001587538	pathogenic	Familial cancer of breast	2022-01-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 545984). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 28726808, 31159747). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu211*) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236).
Myriad Genetics, Inc.	RCV001387044	SCV004044213	pathogenic	Familial cancer of breast	2023-05-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV001025144	SCV004362692	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the BARD1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with breast cancer meeting National Comprehensive Cancer Network v.1.2020 guidelines for molecular testing (PMID: 37239058), individuals affected with pancreatic cancer (PMID: 28726808, 29922827, 29982661), a child affected with neuroblastoma (PMID: 36187937), and an individual referred for genetic testing (PMID: 31159747). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.