Submissions for variant NM_032043.3(BRIP1):c.2390A>G (p.Lys797Arg)

gnomAD frequency: 0.00001  dbSNP: rs730881622

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212323	SCV000210816	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast or ovarian cancer, but also in unaffected controls (Easton et al., 2016; Weber-Lassalle et al., 2018; Moyer et al., 2020); Published functional studies show this variant resulted in protein with a shorter half-life than wild type (Moyer et al., 2020); This variant is associated with the following publications: (PMID: 26921362, 31822495, 23613520, 29368626)
Ambry Genetics	RCV000160319	SCV000216023	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.K797R variant (also known as c.2390A>G), located in coding exon 16 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2390. The lysine at codon 797 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in trans with a BRIP1 nonsense mutation in one individual with a clinical diagnosis of Fanconi Anemia (Chandrasekharappa SC et al. Blood, 2013 May;121:e138-48). This alteration has also been reported in 1/1853 cases of breast cancer and 0/2001 controls from a population-based case control study of breast cancer from the United Kingdom (Easton DF et al. J. Med. Genet., 2016 05;53:298-309). In another study, this alteration was detected in 1/2160 early-onset breast cancer cases and 4/1,199 ovarian cancer cases (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000477092	SCV000547294	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 797 of the BRIP1 protein (p.Lys797Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer and clinical features of Fanconi anemia (PMID: 23613520, 26921362, 31822495). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 182330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000663309	SCV000786568	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2018-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160319	SCV000903895	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 797 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study reported this variant as hypomorphic conferring hypersensitivity to DNA interstrand crosslinker and partial protein instability when expressed in BRIP1 deficient cell cultures (PMID: 31822495). This variant has been observed in at least seven individuals affected with breast cancer and ovarian cancer, and in one unaffected individual (PMID: 26921362, 29368626, 31822495, 33471991; Leiden Open Variation Database DB-ID BRIP1_000013) and in an individual age 70 years or older without cancer (https://whi.color.com/variant/17-59793414-T-C). This variant also has been observed in trans with a pathogenic BRIP1 variant in an individual affected with Fanconi anemia (PMID: 23613520). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic with potentially reduced penetrance compared with a traditional pathogenic BRIP1 variant. Medical management should be considered based on the individual's personal and family history.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781178	SCV000919058	uncertain significance	not specified	2018-06-22	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2390A>G (p.Lys797Arg) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 119316 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2390A>G, has been reported in the literature in an individual affected with Breast Cancer (Easton 2016), but was also reported in a healthy individual older than 70 years who has never had cancer (FLOSSIES). The variant has been reported in an individual affected with Fanconi Anemia, with a known pathogenic BRIP1 variant in trans (Chandrasekharappa 2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000160319	SCV002531411	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315951	SCV004019371	uncertain significance	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003315951	SCV004217054	uncertain significance	Familial cancer of breast	2023-07-14	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000781178	SCV001251327	benign	not specified	2019-09-01	no assertion criteria provided	research
Leiden Open Variation Database	RCV001194708	SCV001364471	uncertain significance	Fanconi anemia complementation group J	2013-10-04	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.