Submissions for variant NM_032043.3(BRIP1):c.2255_2256del (p.Lys752fs)

dbSNP: rs730881649

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212320	SCV000210871	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Frameshift 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 17033622, 26315354, 26976419, 29368626, 32359370); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28152038, 26681312, 19763819, 26315354, 17033622, 26976419, 29308099, 26681682, 29368626, 20346647, 30322717, 16116423, 32359370, 26689913, 29625052, 29922827, 28888541, 34326862, 34887416, 34308104, 35626031, 36451132)
Ambry Genetics	RCV000160364	SCV000214477	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	clinical testing	The c.2255_2256delAA pathogenic mutation, located in coding exon 14 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 2255 to 2256, causing a translational frameshift with a predicted alternate stop codon (p.K752Rfs*12). This mutation was seen in conjunction with a second BRIP1 alteration in a patient with Fanconi anemia complementation group J (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5). It has also been seen in patients with breast and/or ovarian cancer (Ramus SJ et al. J Natl Cancer Inst. 2015 Nov;107; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Tung N et al. J Clin Oncol. 2016 May;34:1460-8; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488; Weber-Lasalle N et al. Breast Cancer Res. 2018 Jan;20(1):7). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167986	SCV000218635	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys752Argfs*12) 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 (rs730881649, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ovarian cancer or breast cancer and Fanconi anemia (PMID: 16116423, 26315354, 26681312, 26681682, 26976419). This variant is also known as c.2255_2256delTT. ClinVar contains an entry for this variant (Variation ID: 182372). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000160364	SCV000292165	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-02	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 of the BRIP1 gene, creating a frameshift and 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 with breast cancer (PMID: 17033622, 26681682, 26976419) and ovarian cancer (PMID: 26315354, 26681312, 29368626), as well as in an individual affected with Fanconi anemia (PMID: 16116423). This variant has been identified in 3/251052 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587824	SCV000699686	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60679), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRIP1 variant of 1/16000. In addition, this observation needs to be cautiously considered due to the cohort including individuals that could harbor a BRIP1 phenotype. The variant of interest has been reported in affected individuals with varying phenotypes BrC, OvC and FANCJ, including the variant of interest segregating with disease (BrC) within one family (Seal_2006). In addition, multiple reputable clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Counsyl	RCV000662905	SCV000785827	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2017-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212320	SCV001134013	pathogenic	not provided	2019-03-27	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. This variant has been reported in individuals with breast cancer, ovarian cancer, and Fanconi Anemia complementation group J (FA-J) in the published literature (PMID: 26976419 (2016), 26681312 (2018), 26681312 (2015), 16116423 (2005)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV001781501	SCV002017955	pathogenic	Fanconi anemia complementation group J	2019-03-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160364	SCV002531399	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315959	SCV004019361	pathogenic	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003315959	SCV004214728	pathogenic	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing