ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.442-22_442-13del (rs879254224)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235873 SCV000293883 likely pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated to result in the insertion of 59 nucleotides, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Li 1999, Ang 2007); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Li 1999, Ang 2007, Lin 2016); Not observed in large population cohorts (Lek 2016); Also known as 561-22_561-13del10 or IVS7-22_IVS7-13del10; This variant is associated with the following publications: (PMID: 26824983, 10323242, 18006916)
Invitae RCV000463705 SCV000549418 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-23 criteria provided, single submitter clinical testing This sequence change deletes 10 nucleotides from intron 6 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but could potentially disrupt mRNA splicing. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals of Asian ancestry with breast and/or ovarian cancer (PMID: 18006916, 26221963, 26824983, 10323242), and shown to segregate with breast/ovarian cancer in several of the families (PMID: 10323242, Invitae). Intron 6 is also known as intron 7, and this variant is also known as IVS7-15del10, IVS7-22del10 and g.41251910_41251919 delGTAAAGAACA in the literature. ClinVar contains an entry for this variant (Variation ID: 246362). Experimental studies have shown that this intronic change results in the insertion of 59 nucleotides from intron 6 into the BRCA1 transcript, causing a frameshift and creating a stop codon in exon 7 (PMID: 10323242, 18006916). For these reasons, this variant has been classified as Pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000463705 SCV000897861 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing. Denominator ~16,600. In the GNOMAD NFE population of 63,369 individuals, the frequency of this variant is 0. exact: p=0.04. (PS4_strong) This variant is reported twice on ClinVar. There are additional reports of this variant in: i) Li et al. 1999 Hum Genet 104 201-204: Variant found variant in 2 unrelated Taiwanese families:Br Ca in mother and daughter (age 58 & 28), Br Ca/Ov Ca in mother age 48 and Br Ca in daughter (age 30). ii) Ang et al Cancer Epidem Bio and Prev 2007; 16 (11) two affected sisters. In the remainder of the GNOMAD populations (75,263 individuals, including 8624 East Asians), the frequency of this variant is 0 (PM2). Li et al. 1999 Hum Genet 104 201-204: RT-PCR carried out: an insertion of 59 nucleotides mRNA results in frameshift and premature termination codon in exon 8 (historical exon numbering). AND Ang et al Cancer Epidem Bio and Prev 2007; 16 (11): insertion of 59 nucleotides mRNA. However, only single WT control used. (PS3_mod) Data not included in classification: Li et al. 1999 Hum Genet 104 201-204: variant segregates with disease in two 2 case families. In silico analysis predict effect on splicing: Predicted change at acceptor site 13 bps downstream. MaxEnt: -43.6%; NNSPLICE: -65.0% Other information: Wong et al. 2015 (PLOS1). Patient had a BRCA1 c.442-22-442-13 variant and also a pathogenic variant in BRCA2 c.5645C>A; p.Ser1882*).
Color Health, Inc RCV001189625 SCV001356943 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-27 criteria provided, single submitter clinical testing

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