Submissions for variant NM_032043.3(BRIP1):c.3523A>G (p.Thr1175Ala)

gnomAD frequency: 0.00004  dbSNP: rs372799558

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000525915	SCV000633676	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1175 of the BRIP1 protein (p.Thr1175Ala). This variant is present in population databases (rs372799558, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 461154). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Mendelics	RCV000709524	SCV000839348	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780067	SCV000917089	uncertain significance	not specified	2021-01-09	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3523A>G (p.Thr1175Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250646 control chromosomes. 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.3523A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000989975	SCV001140737	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001020519	SCV001182008	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	The p.T1175A variant (also known as c.3523A>G), located in coding exon 19 of the BRIP1 gene, results from an A to G substitution at nucleotide position 3523. The threonine at codon 1175 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is 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. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).
GeneDx	RCV001591213	SCV001824798	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with ovarian cancer (Bhai et al., 2021); This variant is associated with the following publications: (PMID: 32832836, 34326862)