Submissions for variant NM_032043.3(BRIP1):c.629C>A (p.Pro210His)

dbSNP: rs140097800

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214330	SCV000275115	likely benign	Hereditary cancer-predisposing syndrome	2024-09-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000213204	SCV000278894	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25256751)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465031	SCV000547301	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 210 of the BRIP1 protein (p.Pro210His). This variant is present in population databases (rs140097800, gnomAD 0.004%). 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: 231306). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000214330	SCV000689406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 210 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/280186 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.
Mendelics	RCV000990027	SCV001140791	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000990027	SCV004214672	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000213204	SCV004562402	uncertain significance	not provided	2023-08-11	criteria provided, single submitter	clinical testing	The BRIP1 c.629C>A; p.Pro210His variant (rs140097800), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 231306). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (6/128,020 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.139). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213204	SCV005623302	uncertain significance	not provided	2024-05-24	criteria provided, single submitter	clinical testing	The BRIP1 c.629C>A (p.Pro210His) variant has been reported in the published literature in in individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1)). The frequency of this variant in the general population, 0.000047 (6/128020 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000465031	SCV005654140	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000213204	SCV001551667	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Pro210His variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs140097800) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, GeneDx, Invitae, and Color Genomics), and Clinvitae (3x) databases. The variant was identified in a control database in 5 of 274722 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 5 of 125584 chromosomes (freq: 0.00004); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and SouthAsian populations. The p.Pro210 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.