Submissions for variant NM_032043.3(BRIP1):c.1240C>T (p.Gln414Ter)

gnomAD frequency: 0.00001  dbSNP: rs368796923

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129878	SCV000184695	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant has been identified in at least one patient with a personal and family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May;98:801-817). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Counsyl	RCV000409609	SCV000489993	likely pathogenic	Fanconi anemia complementation group J	2016-09-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000411128	SCV000489994	likely pathogenic	Ovarian neoplasm	2016-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000445256	SCV000515873	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual undergoing multi-gene panel testing in a clinical laboratory (PMID: 28152038); This variant is associated with the following publications: (PMID: 29922827, 28152038, 29368626)
Color Diagnostics, LLC DBA Color Health	RCV000129878	SCV000689256	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251108 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701846	SCV000830666	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln414*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs368796923, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141382). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000701846	SCV000893464	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781179	SCV000919060	likely pathogenic	Familial cancer of breast	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1240C>T (p.Gln414X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1871C>A (p.Ser624X), c.2255_2256delAA (p.Lys752fsX12), c.2392C>T (p.Arg798X)). The variant allele was found at a frequency of 4.1e-06 in 245868 control chromosomes (gnomAD). The variant, c.1240C>T, has been reported in the literature with limited information (Hu_2018, La Duca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000781179	SCV004019415	pathogenic	Familial cancer of breast	2023-03-01	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335116	SCV004046096	likely pathogenic	BRIP1-associated familial cancer predisposition		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not been reported in affected individuals in the literature to our knowledge; however, loss-of-function variation in BRIP1 is an established mechanism of disease (PMID: 16116423, 17033622, 21964575). The c.1240C>T (p.Gln414Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251108) and thus presumed to be rare. Based on the available evidence, the c.1240C>T (p.Gln414Ter) variant is classified as Likely Pathogenic.
Baylor Genetics	RCV000781179	SCV004217065	pathogenic	Familial cancer of breast	2023-06-30	criteria provided, single submitter	clinical testing