Submissions for variant NM_032043.3(BRIP1):c.3237T>G (p.Ile1079Met)

gnomAD frequency: 0.00005  dbSNP: rs587781666

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129821	SCV000184635	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The p.I1079M variant (also known as c.3237T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3237. The isoleucine at codon 1079 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well 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	RCV000200144	SCV000255169	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1079 of the BRIP1 protein (p.Ile1079Met). This variant is present in population databases (rs587781666, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141336). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV000662741	SCV000785520	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2017-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758998	SCV000888001	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780068	SCV000917090	uncertain significance	not specified	2018-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3237T>G (p.Ile1079Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 277116 control chromosomes, predominantly at a frequency of 0.00021 within the African subpopulation in the gnomAD database, which does exceed the estimated maximum expected allele frequency for a pathogenic BRIP1 variant by 3-folds. However, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3237T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129821	SCV001339559	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 1079 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 not been reported in individuals affected with hereditary cancer in the literature. In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls; OR=0.442 (95%CI 0.015 to 13.178); p-value=0.469 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000301). This variant has been identified in 5/282650 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.
Sema4, Sema4	RCV000129821	SCV002533683	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315884	SCV004019412	uncertain significance	Familial cancer of breast	2023-03-01	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.
GeneDx	RCV000758998	SCV004021861	uncertain significance	not provided	2023-01-18	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; Has not been previously published as pathogenic or benign to our knowledge