ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1175_1214del (p.Leu392fs) (rs80359874)

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Total submissions: 20
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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) RCV000019234 SCV000282256 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000047372 SCV000075385 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu392Glnfs*5) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. While this variant is present in population databases (rs80359874), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with breast and/or ovarian cancer and prostate cancer (PMID: 7894491, 21324516, 11179017, 22333603, 19648928, 25556971, 23569316, 17688236), and is a recurrent variant in families of British and Irish origin (PMID: 8571953, 10682686). This variant is also known as 1294del40 in the literature. ClinVar contains an entry for this variant (Variation ID: 17665). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000019234 SCV000154017 pathogenic Breast-ovarian cancer, familial 1 2015-08-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131965 SCV000187023 pathogenic Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000159899 SCV000210008 pathogenic not provided 2018-11-24 criteria provided, single submitter clinical testing This deletion of 40 nucleotides in BRCA1 is denoted c.1175_1214del40 at the cDNA level and p.Leu392GlnfsX5 (L392QfsX5) at the protein level. The surrounding sequence is GAAC[del40]AAAT. The deletion causes a frameshift, which changes a Leucine to a Glutamine at codon 392, and creates a premature stop codon at position 5 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.1175_1214del40, previously reported as 1294del40 using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Castilla 1994, Simard 1994, Zhang 2011, Strom 2015). We therefore consider this deletion to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159899 SCV000296286 pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000238898 SCV000296790 pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019234 SCV000324979 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000019234 SCV000564357 pathogenic Breast-ovarian cancer, familial 1 2015-02-10 criteria provided, single submitter clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000019234 SCV000584015 pathogenic Breast-ovarian cancer, familial 1 2017-07-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047372 SCV000591319 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000019234 SCV000593693 pathogenic Breast-ovarian cancer, familial 1 2017-05-12 criteria provided, single submitter clinical testing
Color RCV000131965 SCV000688319 pathogenic Hereditary cancer-predisposing syndrome 2015-01-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047372 SCV000698834 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1175_1214del40 (p.Leu392Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g., c.1236_1237dupAT [p.Leu413fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000082 (1/121238 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Studies have detected this variant in breast and ovarian cancer patient populations, and the variant has been found to cosegregate with disease in families (Neuhausen_AJHG_1996). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159899 SCV000708436 pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000238898 SCV001160141 pathogenic not specified 2018-12-04 criteria provided, single submitter clinical testing The BRCA1 c.1175_1214del; p.Leu392fs variant (rs80359874), also known as 1294del40, is reported in the literature in multiple individuals affected with breast, ovarian, or prostate cancer (Castilla 1994, Castro 2013, Liede 2000, Neuhausen 1996, Ramus 2007, Risch 2001, Robertson 2012, Zhang 2011). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 17665). It is found in the general population with a low overall allele frequency of 0.0008% (2/250822 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 40 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Castro E et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. Liede A et al. Evidence of a founder BRCA1 mutation in Scotland. Br J Cancer. 2000 Feb;82(3):705-11. Neuhausen SL et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet. 1996 Feb;58(2):271-80. Ramus SJ et al. Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat. 2007 Dec;28(12):1207-15. Risch HA et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. Robertson L et al. BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer. 2012 Mar 13;106(6):1234-8. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
OMIM RCV000019234 SCV000039522 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019234 SCV000053566 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019234 SCV000144027 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047372 SCV000587111 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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