Submissions for variant NM_032043.3(BRIP1):c.1984G>A (p.Ala662Thr)

gnomAD frequency: 0.00001  dbSNP: rs571340013

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167392	SCV000218246	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	The p.A662T variant (also known as c.1984G>A), located in coding exon 13 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1984. The alanine at codon 662 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168048	SCV000218701	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 662 of the BRIP1 protein (p.Ala662Thr). This variant is present in population databases (rs571340013, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 187645). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 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.
GeneDx	RCV000521753	SCV000616665	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual(s) with a personal history of breast cancer (PMID: 25452441); This variant is associated with the following publications: (PMID: 25452441)
Color Diagnostics, LLC DBA Color Health	RCV000167392	SCV000684175	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 662 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25452441). This variant has been identified in 4/282732 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987390	SCV004803971	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1984G>A (p.Ala662Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251328 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1984G>A has been reported in the literature in individuals affected with breast cancer (e.g., Couch_2015, Dorling_2021), however has also been reported in unaffected controls (e.g., Dorling_2021). These reports therefore 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. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 33471991). ClinVar contains an entry for this variant (Variation ID: 187645). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV004567346	SCV005059936	uncertain significance	Familial cancer of breast	2023-12-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000168048	SCV005654119	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-02-24	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000521753	SCV002035729	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521753	SCV002037316	uncertain significance	not provided		no assertion criteria provided	clinical testing