ClinVar Genomic variation as it relates to human health

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 missense variant replaces leucine with phenylalanine at codon 340 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26790966) and in an individual affected with esophageal squamous cell carcinoma (PMID: 30833958). In a large breast cancer case-control study, this variant has been observed in 4/60462 cases and 7/53454 controls; OR=0.505 (95%CI 0.148 to 1.726); p-value=0.367 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000156). In a pancreatic cancer case-control study, this variant has been observed in 0/1005 cases and 14/23705 controls (PMID: 32980694). In a prostate cancer case-control study, this variant has been observed in 4/7636 cases and 9/12366 controls; OR=0.7196131 (0.16 to 2.58), P-value=0.7771929 (PMID: 31214711). This variant has also been identified in 3/251306 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.

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 340 of the BRIP1 protein (p.Leu340Phe). This variant is present in population databases (rs755796609, gnomAD 0.02%). This missense change has been observed in individual(s) with biliary tract cancer, breast cancer, esophageal cancer, pancreatic cancer, and/or prostate cancer (PMID: 26790966, 30833958, 31214711, 32068069, 32255556). ClinVar contains an entry for this variant (Variation ID: 407835). 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.

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.

Observed in individuals with breast, pancreatic, prostate, and other cancers, as well as in unaffected controls (PMID: 26790966, 28873162, 30833958, 31214711, 32255556, 32068069); Published functional in vitro studies demonstrate ability to rescue BRIP1 knockout cellular phenotypes similar to wild type with a moderate defect (PMID: 32542039); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26790966, 27150160, 24336570, 26709662, 28873162, 30833958, 31214711, 27107905, Padeganeh2023[Poster], 35186721, 32255556, 32068069, 32542039, 35171259, 36243179, 37885353)

Variant summary: BRIP1 c.1018C>T (p.Leu340Phe) 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 8.1e-06 in 1613952 control chromosomes, predominantly at a frequency of 0.00025 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Breast Cancer phenotype (6.3e-05). c.1018C>T has been reported in the literature in individuals affected with Breast Cancer (Kim_2016) including with classification as VUS (Kwong_2020). The variant has additionally been reported as a VUS in individuals with other cancers including esophageal squamous cell carcinoma (Deng_2019), epithelial ovarian cancer (Yao_2022), pancreatic ductal adenocarcinoma (Cremin_2020), biliary tract cancer (Okawa_2023), and lung cancer (Yi_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in in vitro assays, but retains the ability to restore wild type-level protein activity in cell-based assays (Odermatt_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32255556, 30833958, 27107905, 26790966, 32068069, 32542039, 36243179, 26709662, 35186721, 37885353). ClinVar contains an entry for this variant (Variation ID: 407835). Based on the evidence outlined above, the variant was classified as likely benign.

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

The BRIP1 c.1018C>T variant is predicted to result in the amino acid substitution p.Leu340Phe. This variant has been reported as a variant of uncertain significance in individuals with multiple different cancer types; however, no follow-up studies have confirmed its pathogenicity (Deng et al. 2019. PubMed ID: 30833958; Kim et al. 2016. PubMed ID: 26790966; Yin et al. 2022. PubMed ID: 35171259; Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. It has conflicting classifications of uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.