Submissions for variant NM_032043.3(BRIP1):c.1372G>T (p.Glu458Ter)

gnomAD frequency: 0.00003  dbSNP: rs587780228

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212309	SCV000150032	pathogenic	not provided	2024-02-20	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); This variant is associated with the following publications: (PMID: 26681312, 28709830, 32242007, 26720728, 30716324, 30154229, 31512090, 31589614, 33471991, 29922827, 31341520)
Ambry Genetics	RCV000116123	SCV000217717	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The p.E458* pathogenic mutation (also known as c.1372G>T), located in coding exon 9 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1372. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90; Schoolmeester JK et al. Hum Pathol, 2017 12;70:14-26; Guindalini RSC et al. Clin Cancer Res, 2019 03;25:1786-1794; Arvai KJ et al. Hered Cancer Clin Pract, 2019 Jul;17:19; Subramanian DN et al. Nat Commun, 2020 04;11:1640), including an individual with male breast cancer (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). This mutation has also been detected in a cohort of 315 patients with intraductal papillary mucinous neoplasms (Skaro M et al. Gastroenterology, 2019 05;156:1905-1913). 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.
Color Diagnostics, LLC DBA Color Health	RCV000116123	SCV000537633	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRIP1 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 reported in individuals affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 26681312, 26720728, 28709830, 30154229, 31341520, 31512090) as well as in an individual affected with intraductal papillary mucinous neoplasms (PMID: 30716324). This variant has been identified in 3/279188 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	RCV000473135	SCV000547328	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu458*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, or glioblastoma (PMID: 26681312, 26720728). ClinVar contains an entry for this variant (Variation ID: 128156). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000663293	SCV000786535	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2018-05-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212309	SCV000885120	pathogenic	not provided	2019-12-15	criteria provided, single submitter	clinical testing	The BRIP1 c.1372G>T; p.Glu458Ter variant (rs587780228), is reported in the literature in individuals with a clinical history of ovarian cancer, breast cancer, glioblastoma, or colon polyps (Norquist 2016, Susswein 2016). This variant is classified as pathogenic by several laboratories in ClinVar (Variation ID: 128156). It is observed in the general population at a low overall allele frequency of 0.006% (2/30950 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Norquist BM et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016 Apr;2(4):482-90. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781186	SCV000919068	pathogenic	Familial cancer of breast	2018-11-08	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1372G>T (p.Glu458X) 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. The variant allele was found at a frequency of 6.5e-05 in 30950 control chromosomes (gnomAD). The variant, c.1372G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Norquist_2016, Schoolmeester_2017, Susswein_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212309	SCV001134002	pathogenic	not provided	2018-09-03	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Revvity Omics, Revvity	RCV001781450	SCV002017978	pathogenic	Fanconi anemia complementation group J	2019-09-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116123	SCV002531344	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000473135	SCV002811133	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2022-04-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000781186	SCV004019460	pathogenic	Familial cancer of breast	2023-03-02	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.
Baylor Genetics	RCV000781186	SCV004214610	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing