Submissions for variant NM_032043.3(BRIP1):c.2830C>G (p.Gln944Glu)

gnomAD frequency: 0.00003  dbSNP: rs140233356

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585934	SCV000150058	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate defective BRCA1 binding, decreased homologous recombination, and increased long-tract gene conversions in comparison to control cell lines (PMID: 28911102); Observed in individuals with a personal or family history of breast, ovarian, and prostate cancer (PMID: 18483852, 26921362, 26790966, 26976419, 28796317, 31214711, 30982232, 31742824, 33471991, 35264596); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.2971C>G; This variant is associated with the following publications: (PMID: 18483852, 26976419, 23161009, 26790966, 21964575, 21165771, 19856097, 20346647, 26709662, 26921362, 25256751, 23318652, 25428177, 28796317, 29173497, 31214711, 30295334, 31742824, 32300589, 32426482, 32255556, 32566746, 35681111, 33471991, 30982232, 33309985, 28911102, 35264596, 36243179, 11301010)
Ambry Genetics	RCV000116149	SCV000214613	likely benign	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199089	SCV000255163	benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000411198	SCV000489957	uncertain significance	Fanconi anemia complementation group J	2016-08-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000409338	SCV000489958	uncertain significance	Ovarian neoplasm	2016-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116149	SCV000537546	likely benign	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855583	SCV000699705	likely benign	not specified	2024-07-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000411198	SCV000839363	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030467	SCV001193527	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000411198	SCV001284866	uncertain significance	Fanconi anemia complementation group J	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000116149	SCV002533652	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-15	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000411198	SCV003830163	uncertain significance	Fanconi anemia complementation group J	2022-01-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315655	SCV004019502	uncertain significance	Familial cancer of breast	2023-03-02	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.
PreventionGenetics, part of Exact Sciences	RCV004529951	SCV004120110	uncertain significance	BRIP1-related disorder	2022-09-27	criteria provided, single submitter	clinical testing	The BRIP1 c.2830C>G variant is predicted to result in the amino acid substitution p.Gln944Glu. This variant was reported in individuals with a personal and/or family history of breast cancer, pancreatic ductal adenocarcinoma, and gastric cancer (Cao et al. 2009. PubMed ID: 18483852; Kim et al. 2016. PubMed ID: 26790966; Cremin et al. 2020. PubMed ID: 32255556, Supplementary Table 3; Suzuki et al. 2020. PubMed ID: 32426482, Supplementary Table S6). Functional studies found that although BRIP1 (aka FANCJ) Q944E variant protein levels were comparable to wild type, the Q944E variant protein was defective in interacting with BRCA1 protein (Nath et al. 2017. PubMed ID: 28911102). This variant is reported in 0.24% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59763272-G-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128180/). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492507	SCV004240399	likely benign	Breast and/or ovarian cancer	2022-09-06	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000855583	SCV001364501	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.