rs755796609
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_032043.3(BRIP1):c.1018C>T(p.Leu340Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L340P) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1018C>T | p.Leu340Phe | missense_variant | 8/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1018C>T | p.Leu340Phe | missense_variant | 8/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251306Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135820
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727162
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74452
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2023 | 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 domain (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 1.2e-05 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 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). 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). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments including uncertain significance (n=4), likely benign (n=1), and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Benign, no assertion criteria provided | curation | Leiden Open Variation Database | Aug 13, 2019 | Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | 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. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | 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. - |
BRIP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 27, 2023 | 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 (http://gnomad.broadinstitute.org/variant/17-59878736-G-A). 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. - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 14, 2017 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2022 | 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; Published functional in vitro studies demonstrate ability to rescue BRIP1 knockout cellular phenotypes similar to wild type with a moderate defect (Odermatt et al., 2020); Also known as FANCJ; This variant is associated with the following publications: (PMID: 26790966, 27150160, 24336570, 26709662, 28873162, 30833958, 31214711, 32542039) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at