Submissions for variant NM_032043.3(BRIP1):c.2325T>G (p.Asn775Lys)

dbSNP: rs375146450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206272	SCV000259485	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 775 of the BRIP1 protein (p.Asn775Lys). This variant is present in population databases (rs375146450, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 32255556). ClinVar contains an entry for this variant (Variation ID: 219556). 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%. 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.
GeneDx	RCV000520323	SCV000618232	uncertain significance	not provided	2023-12-20	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; This variant is associated with the following publications: (PMID: 31159747, 33471991, 11301010, 32255556, 34299313)
Ambry Genetics	RCV000571248	SCV000666184	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-25	criteria provided, single submitter	clinical testing	The p.N775K variant (also known as c.2325T>G), located in coding exon 15 of the BRIP1 gene, results from a T to G substitution at nucleotide position 2325. The asparagine at codon 775 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration has also been identified in an individual diagnosed with pancreatic cancer (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571248	SCV000689330	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 775 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with a personal or family history of breast and/or ovarian cancer (PMID: 31159747, 33471991, 34299313 ) and pancreatic cancer (PMID: 32255556), as well as in an unaffected control individual (PMID: 33471991). This variant has been identified in 1/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneKor MSA	RCV000571248	SCV000821959	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731436	SCV001983671	uncertain significance	not specified	2021-09-16	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2325T>G (p.Asn775Lys) results in a non-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 allele was found at a frequency of 4e-06 in 251310 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2325T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and pancreatic ductal adenocarcinoma (Tsaousis_2019, Cremin_2020, Dorling_2021, Guglielmi_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001731436	SCV002760975	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462365	SCV004217113	uncertain significance	Familial cancer of breast	2023-05-24	criteria provided, single submitter	clinical testing