ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.475+1G>T (rs81002797)

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Total submissions: 9
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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) RCV000113645 SCV001161654 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998544
Invitae RCV000044483 SCV000072496 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with a personal and/or family history of breast or ovarian cancer (PMID: 18703817, 24156927, 28724667, 29446198). This variant is also known as IVS5+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 51709). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30883759). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162896 SCV000213383 pathogenic Hereditary cancer-predisposing syndrome 2019-01-28 criteria provided, single submitter clinical testing The c.475+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the BRCA2 gene. This alteration has been identified in multiple breast and/or ovarian cancer families to date (Palma MD et al. Cancer Res. 2008 Sep;68:7006-14; Tea MK et al. Maturitas. 2014 Jan;77:68-72). Of note, this alteration is also designated as IVS5+1G>T in published literature. While no functional studies for this alteration are available, an alteration at the same location, c.475+1G>A, was found to cause skipping of coding exon 4 leading to a premature termination codon (Colombo M et al. PLoS One. 2013 Feb;8:e57173). 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.
GeneDx RCV000255387 SCV000322287 pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.475+1G>T or IVS5+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 5 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 703+1G>T. This variant destroys a canonical splice donor 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 has been reported in several individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (Palma 2008, Tea 2014). Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113645 SCV000327080 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255387 SCV000600606 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162896 SCV000683650 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044483 SCV000694799 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The c.475+1G>T in a BRCA2 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical acceptor sequence, but functional studies are yet to be conducted to confirm those predictions. The variant has been reported in several affected individuals from HBOC families. The variant is absent from ExAC. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113645 SCV000146934 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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