Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007294.4(BRCA1):c.135-18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,534,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3
Dec 16, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jan 17, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Uncertain:2
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 17, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing; Also known as 254-18T>G; This variant is associated with the following publications: (PMID: 26913838, 23239986, 21523855, 30472649, 32623769, 31131967, 31343793) -
Hereditary breast ovarian cancer syndrome Uncertain:2
Mar 01, 2019
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research
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Sep 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change falls in intron 3 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is present in population databases (rs80358085, gnomAD 0.0009%). This variant has been observed in individual(s) with a personal and/or family history of breast, sarcoma, and prostate cancer (PMID: 23239986, 31343793). This variant is also known as IVS4-18T>G. ClinVar contains an entry for this variant (Variation ID: 54214). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 23239986, 31343793; internal data). 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. -
not specified Uncertain:1
Jul 10, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.135-18T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Experimental evidence demonstrated the variant to marginally impair proper processing of BRCA1 pre-mRNA as it causes an approximately three-fold increased abundance of BRCA1 transcripts lacking exon 4 compared to controls (Wappenschmidt_2012, Montalban_2019). The variant allele was found at a frequency of 4.1e-06 in 242402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.135-18T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Wappenschmidt_2012, Montalban_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.7235insG, p.Thr2412SerfsX2; UMD), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 31343793, 23239986). Six ClinVar submitters have assessed the variant since 2014: all six classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -