ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4485-1G>A (rs80358189)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000112343 SCV000221033 pathogenic Breast-ovarian cancer, familial 1 2015-01-15 criteria provided, single submitter literature only
GeneDx RCV000235386 SCV000293181 pathogenic not provided 2015-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4485-1G>A or IVS13-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 13 of the BRCA1 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also known as BRCA1 c.4604-1G>A or IVS14-1G>A by alternative nomenclature, has been reported in at least two hereditary breast/ovarian cancer families (Liede 2002). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112343 SCV000296365 pathogenic Breast-ovarian cancer, familial 1 2015-07-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112343 SCV000325984 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580034 SCV000683190 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496695 SCV000699153 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4485-1G>A variant involves the alteration of a non-conserved intronic nucleotide, at a location known to affect splicing, which 4/5 splice prediction tools predict a potential affect on splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/118768 (1/59382), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. However, these observations need to be cautiously considered due the cohort harboring individuals that could have a BRCA1 phenotype. Multiple publications cite the variant in affected individuals, in particular, individuals from Pakistan and has been indicated to be a founder mutation. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762999 SCV000893444 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580034 SCV001184311 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing The c.4485-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 13 of the BRCA1 gene. This alteration has been reported in Pakistani families with breast and/or ovarian cancer (Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Rashid MU et al. BMC Cancer, 2016 08;16:673). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000496695 SCV001575609 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80358189, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12181777, 27553291, 29446198, 31528241). This variant is also known as IVS14-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55213). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112343 SCV000145102 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 RCV000496695 SCV000587402 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353957 SCV000591521 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1, c.4485-1G>A variant was identified in 4 of 922 proband chromosomes (frequency: 0.004) from individuals or families with hereditary breast and ovarian cancer and was not identified in 200 control chromosomes from healthy individuals (Liede 2002); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The mutation was found in multiple case subjects and represents a candidate founder mutation in the Pakistani population (Liede 2002). The variant was also identified in dbSNP (ID: rs80358189) “With Pathogenic allele”, HGMD as a “disease causing mutation”, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (2X with “pending” clinical importance), and UMD (3X as a causal variant). The c.4485-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
King Laboratory,University of Washington RCV001171415 SCV001251320 pathogenic Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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