Submissions for variant NM_032043.3(BRIP1):c.679C>T (p.Gln227Ter)

dbSNP: rs45459799

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001025658	SCV001187896	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-25	criteria provided, single submitter	clinical testing	The p.Q227* pathogenic mutation (also known as c.679C>T), located in coding exon 6 of the BRIP1 gene, results from a C to T substitution at nucleotide position 679. This changes the amino acid from a glutamine to a stop codon within coding exon 6. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210339	SCV001381822	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2019-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant has not been reported in the literature in individuals with BRIP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln227*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271613	SCV002555770	likely pathogenic	Fanconi anemia complementation group J	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.679C>T (p.Gln227X) 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 for HBOC. The variant was absent in 250948 control chromosomes (gnomAD). c.679C>T has not been reported in the literature in individuals affected with Fanconi Anemia Complementation Group J but may increase the risk of HBOC. At least one publication reports experimental evidence demonstrating that this variant fail to robustly restore resistance to ICL-inducing agents, cisplatin or mitomycin C (Calvo_2021). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004030873	SCV004932191	pathogenic	Familial cancer of breast	2023-12-19	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.
Leiden Open Variation Database	RCV001194704	SCV001364464	pathogenic	not provided	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Laboratory for Genotyping Development, RIKEN	RCV003160184	SCV002758232	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research