Submissions for variant NM_032043.3(BRIP1):c.2400C>G (p.Tyr800Ter)

dbSNP: rs574552037

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131417	SCV000186395	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	The p.Y800* pathogenic mutation (also known as c.2400C>G), located in coding exon 16 of the BRIP1 gene, results from a C to G substitution at nucleotide position 2400. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. This mutation was reported in conjunction with a second truncating mutation in a Fanconi anemia type J (FA-J) patient (Levran O et al. Nat. Genet. 2005 Sep;37:931-3). This mutation has also been reported in individuals with a personal and/or family history of ovarian and/or breast cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Meiss AE et al. Hum Pathol, 2018 12;82:20-31; Arvai KJ et al. Hered Cancer Clin Pract, 2019 Jul;17:19; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx	RCV000254652	SCV000210817	pathogenic	not provided	2023-09-29	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; Also known as c.2541C>G; This variant is associated with the following publications: (PMID: 26315354, 28152038, 29368626, 32295079, 29922827, 28888541, 26681312, 26720728, 23644138, 30322717, 31980526, 26689913, 29625052, 34308104, 35874679, 33804961, 33471991, 29958926, 32359370, 34887416, 31341520, 16116424)
Invitae	RCV000205848	SCV000260437	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr800*) 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 (rs574552037, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Fanconi anemia type J (PMID: 16116424, 26315354). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2541C>G. ClinVar contains an entry for this variant (Variation ID: 142343). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131417	SCV000684211	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 17 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 over 10 individuals affected with breast and ovarian cancer (PMID: 26315354, 29368626, 29958926, 32359370) and peritoneal cancer (PMID: 26720728) and in one individual age 70 years or older without cancer in the FLOSSIES database. This variant has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000008). This variant has also been reported in the compound heterozygous state with a second BRIP1 mutation in an individual affected with Fanconi anemia (PMID: 16116424). This variant has been identified in 6/248886 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	RCV000588697	SCV000699692	pathogenic	Fanconi anemia complementation group J	2021-06-16	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2400C>G (p.Tyr800X) 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 2.8e-05 in 360186 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Fanconi Anemia Complementation Group J (2.8e-05 vs 0.0004), allowing no conclusion about variant significance. In addition, this variant has also been reported in 1 / 7325 European American woman who was older than age 70, and cancer free (in the FLOSSIES database). The variant, c.2400C>G, has been reported in the literature in a compound heterozygous individual affected with Fanconi Anemia Complementation Group J (FANCJ), who carried a pathogenic BRIP1 variant in trans (Levran_2005). In addition, the variant was also reported in heterozygous state in several individuals affected with ovarian cancer, breast cancer and other tumor phenotypes (e.g. Norquist_2016, Ramus_2015, Weber-Lassalle_2018, Susswein_2016). A recent large case-control study evaluating breast cancer (BrC) cases and controls in the Breast Cancer Association Consortium (BCAC), reported no risk association with familial breast cancer for BRIP1 truncating variants (Dorling_2021). However, a recent meta-analysis found a moderate risk association for BRIP1 truncating variants (including the variant of interest) with ovarian cancer (overall odds ratio (OR) = 4.94, 95% CIs: 4.07-6.00, p <0.0001; Suszynska_2020). At least one publication reported lack of protein expression on immunoblot analysis in cells derived from a FANCJ patient, though the presence of a truncated protein couldn't be excluded, as the antibodies used bound the C terminus (Levran_2005). However, a truncating variant at this protein level (i.e. amino acid 800) is also expected to have a detrimental effect on protein function, as the BRCA1-BRIP1 interaction domain lies in residues 888-1063 (UniProt, PMID: 11301010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000131417	SCV002531413	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272137	SCV002556775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-03-17	criteria provided, single submitter	clinical testing	PS4, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254652	SCV004026880	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003335124	SCV004045370	pathogenic	Familial cancer of breast	2023-06-06	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	RCV003335124	SCV004217028	likely pathogenic	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000588697	SCV001364473	pathogenic	Fanconi anemia complementation group J	2011-02-07	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
CZECANCA consortium	RCV001270930	SCV001451734	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV003155923	SCV002588951	pathogenic	Ovarian cancer	2022-08-26	no assertion criteria provided	clinical testing