ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3642_3643del (p.Asn1215fs)

dbSNP: rs80357805
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Total submissions: 10
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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) RCV000112144 SCV000299985 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000215002 SCV000274331 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The c.3642_3643delGA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3642 to 3643, causing a translational frameshift with a predicted alternate stop codon (p.N1215Lfs*3). This mutation (designated as 3761-3762delGA) has previously been reported in a family with three relatives affected with breast and/or ovarian cancer (Machackova E et al. Hum. Mutat. 2001 Dec; 18(6):545). In addition to the clinical data presented in the literature, 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112144 SCV000325712 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657207 SCV000778933 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA1 is denoted c.3642_3643delGA at the cDNA level and p.Asn1215LeufsX3 (N1215LfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delGA]ACTT. The deletion causes a frameshift which changes an Asparagine to a Leucine at codon 1215, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3642_3643delGA, also reported as BRCA1 3761_3762delGA using alternate nomenclature, has been reported in association with breast and ovarian cancer (Machackova 2001, Foretova 2004). We consider this variant to be pathogenic.
PreventionGenetics, part of Exact Sciences RCV000657207 SCV000806938 pathogenic not provided 2017-08-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779903 SCV000916805 pathogenic Hereditary breast ovarian cancer syndrome 2018-09-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3642_3643delGA (p.Asn1215LeufsX3) 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. The variant was absent in 246070 control chromosomes (gnomAD). The variant, c.3642_3643delGA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Machackova_2001, Machackova_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000779903 SCV001198902 pathogenic Hereditary breast ovarian cancer syndrome 2023-08-18 criteria provided, single submitter clinical testing This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11748848, 18489799). This variant is also known as 3761_3762delGA. ClinVar contains an entry for this variant (Variation ID: 54950). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1215Leufs*3) 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).
All of Us Research Program, National Institutes of Health RCV004803987 SCV005428515 pathogenic BRCA1-related cancer predisposition 2024-07-10 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 3 unrelated individuals affected with breast or ovarian cancer and at 10 suspected hereditary breast and ovarian cancer families (PMID: 11748848, 18489799, 31341520, 31409081). A multifactorial analysis has reported a likelihood ratio (LR) for pathogenicity based on health history of log(LR) = 0.2028528005 (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112144 SCV000144821 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2006-07-19 no assertion criteria provided clinical testing
CZECANCA consortium RCV001271014 SCV001451826 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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