Submissions for variant NM_032043.3(BRIP1):c.2158G>A (p.Val720Met)

dbSNP: rs1555591459

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581314	SCV000689319	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800859	SCV000940599	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 720 of the BRIP1 protein (p.Val720Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 491433). 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.
Ambry Genetics	RCV000581314	SCV001175352	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	The p.V720M variant (also known as c.2158G>A), located in coding exon 14 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2158. The valine at codon 720 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not 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.
Baylor Genetics	RCV003459440	SCV004217031	uncertain significance	Familial cancer of breast	2023-08-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357775	SCV001553345	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Val720Met variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, Zhejiang Colon Cancer Databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Val720 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the DNA helicase (DNA repair), Rad3 type Helicase, ATP-dependent, c2 type functional domain(s) increasing the likelihood that it may have clinical significance. A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.Val720Met variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.