Submissions for variant NM_032043.3(BRIP1):c.1735C>T (p.Arg579Cys)

gnomAD frequency: 0.00034  dbSNP: rs28997571

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212315	SCV000150039	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, pancreatic, colorectal, or other cancers (PMID: 17033622, 25186627, 26921362, 28135145, 28767289, 31822495, 34326862, 33471991, 36315513, 36845387); 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: 29478780, 28135145, 26921362, 25186627, 28767289, 28301460, 31822495, 33471991, 32659497, 17033622, 36845387, 34326862, 36315513)
Ambry Genetics	RCV000116130	SCV000186447	benign	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196018	SCV000255150	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 579 of the BRIP1 protein (p.Arg579Cys). This variant is present in population databases (rs28997571, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or pancreatic cancer (PMID: 25186627, 26921362, 28135145, 28767289, 31822495, 34326862, 36315513). ClinVar contains an entry for this variant (Variation ID: 128162). 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.
Counsyl	RCV000412043	SCV000490015	uncertain significance	Fanconi anemia complementation group J	2016-09-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000410174	SCV000490016	uncertain significance	Ovarian neoplasm	2016-09-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000412043	SCV000839377	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212315	SCV000885123	uncertain significance	not provided	2018-05-06	criteria provided, single submitter	clinical testing	The BRIP1 c.1735C>T; p.Arg579Cys variant (rs28997571) is reported in the germline of individuals with different cancer types, including breast cancer (Easton 2016, Shindo 2017, Tung 2015, Yurgelun 2017), but is also reported in healthy controls (Easton 2016). This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 128162). It is found in the general population with an overall allele frequency of 0.01% (35/277158 alleles) in the Genome Aggregation Database. The arginine at codon 579 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg579Cys variant is uncertain at this time. REFERENCES Easton DF et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016 May;53(5):298-309. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212315	SCV000887984	uncertain significance	not provided	2019-02-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116130	SCV000902711	likely benign	Hereditary cancer-predisposing syndrome	2015-08-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212315	SCV001151388	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000412043	SCV001280774	uncertain significance	Fanconi anemia complementation group J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192970	SCV001361464	likely benign	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1735C>T (p.Arg579Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 261914 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1735C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality (examples, Seal_2006, Tung_2015, Easton_2016, Dorling_2021, Moyer_2020, McDonald_2022). In addition, the variant has been reported in individuals with pancreatic cancer (Shindo_2017), colorectal cancer (Yurgelun_2017) and in unaffected subjects from control cohorts (Dorling_2021, Diaz-Velasquez_2023). 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. 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=9, Likely benign, n=1, Benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000116130	SCV002531374	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315649	SCV004019463	uncertain significance	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004528811	SCV000807123	uncertain significance	BRIP1-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The BRIP1 c.1735C>T variant is predicted to result in the amino acid substitution p.Arg579Cys. This variant has been reported in patients with colorectal cancer (Easton et al. 2016. PubMed ID: 26921362; Yurgelun et al. 2017. PubMed ID: 28135145), pancreatic adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289), and breast cancer (Tung et al. 2015. PubMed ID: 25186627). This variant is reported in 0.088% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128162/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000412043	SCV001554172	uncertain significance	Fanconi anemia complementation group J		no assertion criteria provided	clinical testing	The BRIP1 p.Arg579Cys variant was identified in 4 of 31004 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer, pancreatic cancer or colorectal cancer and was present in 1 of 10484 control chromosomes (frequency: 0.0001) from healthy individuals (Easton 2016, Shindo 2017, Tung 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs28997571) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Counsyl and six other submitters; and as likely benign by Color). The variant was identified in control databases in 35 of 277158 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 24 of 24026 chromosomes (freq: 0.001), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 7 of 126668 chromosomes (freq: 0.00006), and Ashkenazi Jewish in 2 of 10150 chromosomes (freq: 0.00019); it was not observed in the East Asian, Finnish, or South Asian populations. The p.Arg579 residue is not conserved in mammals and four out of five 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.