ClinVar Genomic variation as it relates to human health

The BRIP1 c.1255C>T (p.Arg419Trp) missense change has a maximum subpopulation frequency of 0.059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ovarian and breast cancer, melanoma, colorectal cancer, hereditary prostate cancer and sporadic pancreatic ductal adenocarcinoma (PMID: 19935797, 26315354, 28135145, 28767289, 29368626, 30414346, 31206626, 32283892, 32659497). To our knowledge, this variant has not been reported in the literature in individuals with Fanconi anemia. In addition, this variant was observed in unaffected controls (PMID: 29368626), and in five individuals reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance.

Criteria applied: PP3

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian, breast, prostate, melanoma, pancreatic, colorectal, and other cancers (PMID: 19935797, 26315354, 26921362, 28135145, 29368626, 30651582, 30414346, 32659497, 34326862, 35534704, 33850299); This variant is associated with the following publications: (PMID: 27150160, 29368626, 19935797, 12872252, 24728327, 26315354, 28135145, 26921362, 23555315, 28767289, 30414346, 31159747, 30651582, 32659497, 32283892, 33471991, 35467778, 34284872, 32658311, 29641532, 34326862, 35534704, 33850299)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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.

In the published literature, this variant has been reported in individuals with melanoma (PMID: 30414346 (2019)), prostate (PMIDs: 35467778 (2022), 19935797 (2009)), breast and/or ovarian (PMIDs: 34284872 (2022), 33471991 (2021), 26315354 (2019)), or colorectal cancer (PMID: 32283892 (2020)), as well as in healthy controls (PMIDs: 32658311 (2021), 33471991 (2021), 26315354 (2019), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1). The frequency of this variant in the general population, 0.00059 (18/30608 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.

Variant summary: BRIP1 c.1255C>T (p.Arg419Trp) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type (IPR006554) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277550 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 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 South Asian origin. The variant was also found in 5/7325 European American women over the age of 70 with no history of cancer (carrier freq=0.0006826, FLOSSIES database). c.1255C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer, Pancreatic Cancer, Melanoma, Prostate Cancer, and Colorectal Cancer and in unaffected controls (e.g. Ray_2009, Haiman_2013, Ramus_2015, Easton_2016, Yurgelun_2017, Shindo_2017, Potjer_2018, Lassalle_2018, Schubert_2019, Krivokuca_2019, Wang_2019, Dorling_2021, Brady_2022, Krivokuca_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported at our laboratory (CHEK2 c.1100delC [p.Thr367fs], ClinVar: 128042) and in the literature (BRCA1 c.5266dup, [p.Gln1756fs], ClinVar: 17677; Krivokuca_2022), providing supporting evidence for a benign role. Twenty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: 17 classify the variant as uncertain significance and 3 as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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.

According to the ACMG SVI adaptation criteria we chose these criteria: BS1 (supporting benign): 84x het in gnomAD non Cancer, in V4 432X, BS2 (strong benign): 1x homzygous in gnomAD nonCancer, in v4 2X

The BRIP1 p.Arg419Trp variant was identified in 6 of 6936 proband chromosomes (frequency: 0.001) from individuals or families with prostate or ovarian cancer and was present in 2 of 8336 control chromosomes (frequency: 0.0002) from healthy individuals (Bodian 2014, Ramus 2015, Ray 2009). The variant was also identified in dbSNP (ID: rs150624408) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, Color Genomics, GeneDx, and 4 clinical laboratories), Clinvitae, MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic database. The variant was identified in control databases in 95 of 276856 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: include African in 3 of 24020 chromosomes (freq: 0.0001), “Other” in 6 of 6460 chromosomes (freq: 0.001), Latino in 5 of 34350 chromosomes (freq: 0.0001), European in 56 of 126446 chromosomes (freq: 0.0004), Ashkenazi Jewish in 4 of 10148 chromosomes (freq: 0.0004), East Asian in 2 of 18866 chromosomes (freq: 0.0001), Finnish in 1 of 25786 chromosomes (freq: 0.00004), and South Asian in 18 of 30780 chromosomes (freq: 0.001). The p.Arg419 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 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.

The BRIP1 c.1255C>T variant is predicted to result in the amino acid substitution p.Arg419Trp. This variant has been observed in individuals with breast, prostate, ovarian, colorectal and pancreatic cancer, as well as in healthy control individuals (Rutter et al. 2003. PubMed ID: 12872252; Ray et al. 2009. PubMed ID: 19935797; Table S1, Bodian et al. 2014. PubMed ID: 24728327 Ramus et al. 2015. PubMed ID: 26315354; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.059% of alleles in individuals of South Asian 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/128153/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.