Submissions for variant NM_032043.3(BRIP1):c.2863A>C (p.Asn955His)

gnomAD frequency: 0.00005  dbSNP: rs587782244

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130948	SCV000185862	likely benign	Hereditary cancer-predisposing syndrome	2024-09-04	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	RCV000367894	SCV000329163	uncertain significance	not provided	2024-04-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer (PMID: 21409391, 25186627, 26921362, 33471991, 35467778); This variant is associated with the following publications: (PMID: 21409391, 26921362, 25186627, 11301010, 33471991, 35467778)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464105	SCV000547355	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 955 of the BRIP1 protein (p.Asn955His). This variant is present in population databases (rs587782244, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 21409391, 25186627, 35467778). ClinVar contains an entry for this variant (Variation ID: 142113). 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 not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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	RCV000130948	SCV000903150	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 955 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 4/282132 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000367894	SCV001134019	uncertain significance	not provided	2024-03-12	criteria provided, single submitter	clinical testing	The BRIP1 c.2863A>C (p.Asn955His) variant in the BRIP1 gene. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 21409391 (2011), 25186627 (2015), 26921362 (2016), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). The frequency of this variant in the general population, 0.000031 (4/128866 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192822	SCV001361197	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2863A>C (p.Asn955His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250742 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2863A>C has been reported in the literature in individuals affected with breast an/or ovarian cancer, and prostate cancer, all without evidence of causality (e.g. Wong_2011, Tung_2015, Easton_2016, Brady_2022). These report(s) 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: 21409391, 25186627, 26921362, 35467778). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254681	SCV002525947	uncertain significance	Fanconi anemia complementation group J	2022-02-17	criteria provided, single submitter	clinical testing	The BRIP1 c.2863A>C (p.Asn955His) missense change has a maximum frequency of 0.0031% in gnomAD v2.1.1 ( https://gnomad.broadinstitute.org/variant/17-59763239-T-G?dataset=gnomad_r2_1 ). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 21409391, 25186627, 26921362). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/17-59763239-T-G). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Fulgent Genetics, Fulgent Genetics	RCV000464105	SCV005654098	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-05-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000367894	SCV001551384	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRIP1 p.Asn955His variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer (Wong 2011). The variant was also identified in dbSNP (ID: rs587782244) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Gene Dx, and Color). The variant was identified in control databases in 4 of 276552 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 4 of 126408 chromosomes (freq: 0.00003), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Asn955 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
PreventionGenetics, part of Exact Sciences	RCV004532567	SCV004116726	uncertain significance	BRIP1-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The BRIP1 c.2863A>C variant is predicted to result in the amino acid substitution p.Asn955His. This variant has been reported in patients with a personal and/or family history of breast or ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2015. PubMed ID: 25186627; Easton. 2016. PubMed ID: 26921362). It has also been reported in an individual with prostate cancer (Table S5, Brady et al. 2022. PubMed ID: 35467778). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as uncertain by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/142113/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.