Submissions for variant NM_032043.3(BRIP1):c.1198G>T (p.Asp400Tyr)

gnomAD frequency: 0.00001  dbSNP: rs764711572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196847	SCV000255145	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 400 of the BRIP1 protein (p.Asp400Tyr). This variant is present in population databases (rs764711572, gnomAD 0.003%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754, 30414346). ClinVar contains an entry for this variant (Variation ID: 216785). Advanced 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 at Invitae 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.
Ambry Genetics	RCV000215891	SCV000275090	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.D400Y variant (also known as c.1198G>T), located in coding exon 8 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1198. The aspartic acid at codon 400 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in 2/976 alleles from a cohort of Dutch melanomaprone families (Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464). This alteration was detected in 3/1197 patients with breast cancer who underwent genetic testing (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This amino acid position is well 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.
GeneDx	RCV000219685	SCV000278896	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer, melanoma, and a Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015; Weber-Lassalle et al., 2018; Potjer et al., 2019; Abdel-Razeq et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 30414346, 29368626, 35402282)
Color Diagnostics, LLC DBA Color Health	RCV000215891	SCV000689254	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 400 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 Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754) and in two individuals with melanoma (PMID: 30414346). This variant has been identified in 3/250882 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465561	SCV002760985	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462341	SCV004214763	uncertain significance	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing