Submissions for variant NM_032043.3(BRIP1):c.1871C>A (p.Ser624Ter)

gnomAD frequency: 0.00006  dbSNP: rs587781321

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129060	SCV000183760	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The p.S624* pathogenic mutation (also known as c.1871C>A), located in coding exon 12 of the BRIP1 gene, results from a C to A substitution at nucleotide position 1871. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration has been reported in 1/429 ovarian cancer cases and 0/557 controls (Kanchi KL et al. Nat Commun. 2014;5:3156), in 2/2000 women with hereditary breast cancer and 0/1997 controls (Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9), and in a patient diagnosed with serous ovarian cancer at age 68 (Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90). 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	RCV000254651	SCV000210847	pathogenic	not provided	2023-10-26	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: 30322717, 24763289, 24448499, 26689913, 26786923, 26720728, 29625052, 26315354, 26921362, 30612635, 32427313, 29922827, 28888541, 21964575, 17033622, 32830346, 33471991, 16116423, 35626031)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228701	SCV000290992	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser624*) 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 (rs587781321, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 26315354, 26720728, 26921362). ClinVar contains an entry for this variant (Variation ID: 140852). Studies have shown that this premature translational stop signal is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254651	SCV000600895	pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.000046 (6/129134 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with ovarian cancer (PMIDs: 30322717 (2018), 26720728 (2016), 26315354 (2015), 24448499 (2014)), breast cancer (PMIDs: 32427313 (2020), 26921362 (2016), 26786923 (2016)), endometrial cancer (PMID: 30612635 (2019)), and renal cell carcinoma (PMID: 32830346 (2021)). Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000576387	SCV000677799	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2017-04-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129060	SCV000689288	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 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 breast and ovarian cancer (PMID: 26315354, 26689913, 26720728, 26786923, 26921362, 29625052). This variant has been identified in 7/282740 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	RCV000589135	SCV000699678	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1871C>A (p.Ser624X) 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. The variant allele was found at a frequency of 2e-05 in 255438 control chromosomes. The variant, c.1871C>A, has been reported in the literature in multiple individuals affected with breast- and/or ovarian cancer (eg. Kanchi_2014, LaDuca_2014, Ramus_2015, Thompson_2016, Huang_2018, etc). 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. Eight 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.
Revvity Omics, Revvity	RCV001781464	SCV002017983	pathogenic	Fanconi anemia complementation group J	2021-12-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129060	SCV002531376	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315870	SCV004019396	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	RCV003335111	SCV004046419	pathogenic	BRIP1-associated familial cancer predisposition		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 13 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1871C>A (p.Ser624Ter) variant has been previously reported as a heterozygous change in multiple unrelated individuals with ovarian cancer (PMID: 26315354, 26720728, 24763289, 30322717, 29625052), breast cancer (PMID: 26921362), and endometrial cancer (PMID: 30612635). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (7/282740) and thus is presumed to be rare. Based on the available evidence, the c.1871C>A (p.Ser624Ter) variant is classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387506	SCV004099082	pathogenic	Malignant tumor of breast	2023-08-28	criteria provided, single submitter	clinical testing	PVS1, PS4
Baylor Genetics	RCV003315870	SCV004214720	pathogenic	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000254651	SCV003839289	pathogenic	not provided	2022-03-16	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.1871C>A, which results in the creation of a premature stop codon at amino acid position 624, p.Ser624*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRIP1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.0046% in the non-Finnish European subpopulation (dbSNP rs587781321). This sequence change has previously been described in multiple individuals with ovarian cancer and breast cancer (PMID: 30322717, 32359370, 26720728, 26786923, 26921362, 29625052, 26315354). Loss of function variants are known to be pathogenic in BRIP1 and occur both upstream and downstream of the p.Ser624* variant. Based on these evidences, this sequence change is classified as pathogenic.