Submissions for variant NM_032043.3(BRIP1):c.2914G>A (p.Val972Ile)

gnomAD frequency: 0.00001  dbSNP: rs786203224

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166442	SCV000217237	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	The p.V972I variant (also known as c.2914G>A), located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2914. The valine at codon 972 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in an individual with pancreatic cancer (Hu H et al. J Am Coll Surg 2020 11;231(5):527-535.e14). This amino acid position is poorly 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.
Invitae	RCV000472014	SCV000547336	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 972 of the BRIP1 protein (p.Val972Ile). This variant is present in population databases (rs786203224, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer or breast cancer (PMID: 28767289, 35264596). ClinVar contains an entry for this variant (Variation ID: 186793). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000662959	SCV000785930	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2018-01-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000709533	SCV000839359	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166442	SCV000909754	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 972 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 an individual affected with pancreatic cancer (PMID: 28767289). This variant has also been identified in 2/250750 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.
Mendelics	RCV000989986	SCV001140748	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV002259316	SCV002538707	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with pancreatic cancer (Shindo 2017, Hu 2020); This variant is associated with the following publications: (PMID: 11301010, 28767289, 32659497)
Myriad Genetics, Inc.	RCV000989986	SCV004019368	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.