Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000165601 | SCV000216335 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-29 | criteria provided, single submitter | clinical testing | The p.M28K variant (also known as c.83T>A), located in coding exon 1 of the BRIP1 gene, results from a T to A substitution at nucleotide position 83. The methionine at codon 28 is replaced by lysine, an amino acid with similar properties. This alteration was identified in an cohort of 1058 unselected individuals with colon cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV001064592 | SCV001229502 | uncertain significance | Familial cancer of breast; Fanconi anemia complementation group J | 2023-06-04 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 28 of the BRIP1 protein (p.Met28Lys). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function. ClinVar contains an entry for this variant (Variation ID: 186074). |
Color Diagnostics, |
RCV000165601 | SCV001351682 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-12-15 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with lysine at codon 28 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 colorectal cancer (PMID: 28135145). This variant has not been identified 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, |
RCV004767106 | SCV005381268 | uncertain significance | not specified | 2024-08-07 | criteria provided, single submitter | clinical testing | Variant summary: BRIP1 c.83T>A (p.Met28Lys) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251200 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.83T>A has been reported in the literature as a VUS in settings of multigene panel testing in one individual in a cohort affected with colorectal cancer (example, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Fanconi Anemia Complementation Group J or a BRIP1-associated cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 186074). Based on the evidence outlined above, the variant was classified as uncertain significance. |