Submissions for variant NM_032043.3(BRIP1):c.2885T>C (p.Ile962Thr)

gnomAD frequency: 0.00001  dbSNP: rs786201632

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164008	SCV000214612	likely benign	Hereditary cancer-predisposing syndrome	2024-04-26	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	RCV000197368	SCV000255165	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164008	SCV000689360	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797647	SCV000699708	uncertain significance	not specified	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2885T>C (p.Ile962Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2885T>C has been reported in the literature citing the ClinVar database classification as a VUS (as of May-2019) among a discovery cohort of individuals affected with early onset breast cancer (example, Moyer_2020). These report(s) 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000662667	SCV000785366	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-07-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316014	SCV004019362	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.
PreventionGenetics, part of Exact Sciences	RCV004732724	SCV005362042	uncertain significance	BRIP1-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The BRIP1 c.2885T>C variant is predicted to result in the amino acid substitution p.Ile962Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184706/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.