ClinVar Genomic variation as it relates to human health

This missense variant replaces aspartic acid with tyrosine at codon 184 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). An RNA study has indicated that this variant causes an in-frame skipping of exon 5 (PMID: 30230034). To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26845104, 26921362, 28503720, 29335925, 29368626, 30230034) and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), as well as in unaffected control individuals (PMID: 26921362, 29368626). In a large breast cancer case-control study, this variant was observed in 17/60466 cases and 15/53461 unaffected controls (OR=1.002; 95%CI 0.5 to 2.007; p-value=1; Leiden Open Variation Database DB-ID BRIP1_000202) (PMID: 33471991). This variant has been identified in 28/282718 chromosomes (27/129082 Non-Finnish European 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.

Variant summary: BRIP1 c.550G>T (p.Asp184Tyr) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, a functional study, Velazquez_2019, found the variant to cause exon 5 skipping, suggestive of a potential pathogenic effect due to the disruption of the helicase domain of BRIP1. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Breast Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.550G>T has been reported in the literature in sequencing studies of individuals affected with Breast, Prostate, Pancreatic, Colon, and unidentified cancers as well as in unaffected controls (example, Dudley_2018, Easton_2016, Fostira_2018, Lu_2015, Mouradov_2014, Rummel_2017, Shirts_2015, Tsaousis_2019, Tung_2014, Velazquez_2019, Weber-Lassalle_2018, Yurgelun_2015). One family, described in Velazquez_2019, shows the variant does not segregate with disease, possibly suggesting reduced penetrance. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25186627, 24755471, 26689913, 26845104, 26921362, 28503720, 29335925, 29360161, 29368626, 31159747, 30230034). ClinVar contains an entry for this variant (Variation ID: 143021). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.D184Y variant (also known as c.550G>T), located in coding exon 5 of the BRIP1 gene, results from a G to T substitution at nucleotide position 550. The aspartic acid at codon 184 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been detected in individuals diagnosed with breast or Lynch Syndrome related cancers and in individuals referred for multi-gene panel testing (Tung N et al. Cancer. 2015 Jan;121:25-33; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Rummel SK Breast Cancer Res. Treat. 2017 Aug;164(3):593-601; Fostira F Breast Cancer Res. Treat. 2018 May;169(1):105-113; Tsaousis GN BMC Cancer. 2019 Jun;19(1):535; Lerner-Ellis et al. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-9). In one study, this alteration was observed in 0/706 cases with ovarian cancer, 0/6341 cases with breast cancer and in 2/36687 controls (Weber-Lassalle N et al. Breast Cancer Res. 2018 01;20:7) and in 6/13213 cases of breast cancer and 2/5242 controls (Easton DF J. Med. Genet. 2016 05;53(5):298-309). RNA analyses performed on individuals heterozygous for this alteration have identified both normal transcript, as well as an abnormal transcript lacking exon 5 (Vel&aacute;zquez C et al. Mol. Carcinog. 2018 Sep). This amino acid position is 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.

The BRIP1 c.550G>T (p.Asp184Tyr) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 33471991 (2021), 30613976 (2019), 29368626 (2018), 29335925 (2018), 28503720 (2017), 26921362 (2016), 26845104 (2016)), Lynch syndrome/colorectal cancer (PMIDs: 38060977 (2023), 25980754 (2015)), duodenal cancer (PMID: 38781545 (2024)), and prostate cancer (PMID: 29360161 (2018)), as well as reportedly healthy individuals (PMIDs: 33471991 (2021), 26921362 (2016)). In addition, this variant has been reported to result in the in-frame deletion of exon 5, however the effect on BRIP1 protein function and activity was not assessed (PMID: 30230034 (2019)). The frequency of this variant in the general population, 0.00021 (27/129082 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.

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PP3.

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 184 of the BRIP1 protein (p.Asp184Tyr). This variant is present in population databases (rs201047375, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and Lynch syndrome-associated cancers (PMID: 25186627, 25980754, 26845104, 26921362, 28503720, 29335925, 29368626, 30230034). ClinVar contains an entry for this variant (Variation ID: 143021). 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) has been performed at Invitae 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

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.

Published functional studies suggest that this variant results in exon 5 skipping due to creation of a splice enhancer site (PMID: 30230034); 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: 24755471, 26845104, 26689913, 27498913, 28503720, 25980754, 29335925, 26921362, 26315354, 30230034, 29368626, 31159747, 32756499, 30613976, 33471991, 32885271, 29360161, 35451682, 35534704, 37216690, 35980532)

BRIP1: PS3:Supporting, BP1

The BRIP1 p.Asp184Tyr variant was identified in 11 of 32106 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and Lynch Syndrome and was present in 2 of 10484 control chromosomes (frequency: 0.0002) from healthy individuals (Easton 2016, Rummel 2017, Shirts 2016, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs201047375) as "With Uncertain significance allele", ClinVar (4x, uncertain significance), and Clinvitae (3x, uncertain significance). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 30 of 277086 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24028 chromosomes (freq: 0.00004), other in 1 of 6460 chromosomes (freq: 0.0002), and European in 28 of 126622 chromosomes (freq: 0.0002). The variant was not observed in the Latino, Ashkenazi Jewish, EastAsian, Finnish, and South Asian populations. The identification of this variant together with a co-occurring pathogenic variant in the PALB2 gene (c.661_662delinsTA, p.Val221X) by our laboratory in one individual with breast cancer increases the likelihood this variant does not have clinical significance. The p.Asp184 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the tyrosine variant may impact the protein; however, this information is not predictive enough to assume 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. 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.

The BRIP1 c.550G>T variant is predicted to result in the amino acid substitution p.Asp184Tyr. This variant has been reported in individuals with breast and/or ovarian cancer (Supplementary Table S1, Shirts et al. 2016. PubMed ID: 26845104; Rummel et al. 2017. PubMed ID: 28503720; Fostira et al. 2018. PubMed ID: 29335925; Supplementary Table S5, Tsaousis et al. 2019. PubMed ID: 31159747) and an individual undergoing testing for Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754). One in vitro study indicated that the c.550G>T (p.Asp184Tyr) variant may result exon 5 skipping; however, full-length transcript is also produced (Velázquez et al. 2018. PubMed ID: 30230034). Additionally, this variant has been identified in healthy controls (Easton et al. 2016. PubMed ID: 26921362). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/143021/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.