ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3397_3398del (p.Leu1133fs)

dbSNP: rs80357577
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112085 SCV000282305 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112085 SCV000296363 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-07-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112085 SCV000325647 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226181 SCV003923026 pathogenic Hereditary breast ovarian cancer syndrome 2023-03-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3397_3398delTT (p.Leu1133ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250824 control chromosomes (gnomAD). c.3397_3398delTT has been reported in the literature in individuals with a personal and/or family history of breast and/or ovarian cancers (e.g. Sekine_2001, Rebbeck_2018, Yoshihara_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters, including an expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003226181 SCV004296819 pathogenic Hereditary breast ovarian cancer syndrome 2023-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1133Argfs*7) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 11695708, 31825140). This variant is also known as 3516-3517delTT. ClinVar contains an entry for this variant (Variation ID: 54865). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004609304 SCV005100925 pathogenic Hereditary cancer-predisposing syndrome 2024-05-17 criteria provided, single submitter clinical testing The c.3397_3398delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3397 to 3398, causing a translational frameshift with a predicted alternate stop codon (p.L1133Rfs*7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112085 SCV000144749 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162407 SCV002758469 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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