ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074+3A>G

dbSNP: rs80358181
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255098 SCV000322278 likely pathogenic not provided 2022-04-25 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated to cause aberrant splicing, resulting in skipping of exon 16 or insertion of partial intron 16, both of which are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (Menendez 2012); Observed in individuals with breast and/or ovarian cancer (Menendez 2012, Nakamura 2015, Abdel-Razeq 2018, Arai 2018, Chen 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5193+3A>G and IVS17+3A>G; This variant is associated with the following publications: (PMID: 29409476, 21735045, 24249303, 29659587, 30209399, 31131967, 32295079, 32091409, 29176636)
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000112483 SCV000743382 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV001378309 SCV001575854 likely pathogenic Hereditary breast ovarian cancer syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21735045, 24249303, 29409476, 31368036, 32091409, 32733560, 34290354). This variant is also known as IVS17+3A>G . ClinVar contains an entry for this variant (Variation ID: 55375). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17 and insertion of 153 bp of intron 17 and introduces a premature termination codon (PMID: 21735045). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics RCV002345343 SCV002645957 likely pathogenic Hereditary cancer-predisposing syndrome 2021-12-03 criteria provided, single submitter clinical testing The c.5074+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 15 in the BRCA1 gene. This alteration is also know as IVS17+3G>A in the literature. One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration has been shown to result in aberrant splicing that is subject to nonsense-mediated decay (Menéndez M et al. Breast Cancer Res Treat, 2012 Apr;132:979-92; Ambry internal data).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics RCV000112483 SCV004216926 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV002345343 SCV004360134 likely pathogenic Hereditary cancer-predisposing syndrome 2023-04-24 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +3 position of intron 16 of the BRCA1 gene. An RNA study has shown that this variant causes out-of-frame splicing that is expected to result in an absent or disrupted protein product (PMID: 21735045). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in over 10 individuals and families affected with breast and/or ovarian cancer (PMID: 21735045, 24249303, 28486781, 29409476, 31368036, 32091409). This variant was reported to segregate with breast cancer in a mother and daughter pair (PMID: 21735045), and a multifactorial analysis has reported a likelihood ratio for pathogenicity based on co-segregation of 1.7629 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112483 SCV000145291 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 1999-12-30 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000496317 SCV000587452 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112483 SCV000733601 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000112483 SCV001242049 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
CZECANCA consortium RCV001271029 SCV001451844 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255098 SCV001958335 pathogenic not provided no assertion criteria provided clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000112483 SCV003927196 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-08-29 no assertion criteria provided clinical testing A point mutation in the BRCA1 gene (c.5137+3A>G. This sequence change falls in intron 16 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.this variant has been classified as Likely Pathogenic. Further genetic testing might be considered if clinically indicated.

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