ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.788-800A>G (rs368690455)

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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) RCV000495287 SCV000578290 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics RCV000162699 SCV000213154 likely benign Hereditary cancer-predisposing syndrome 2014-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000442367 SCV000512301 likely benign not specified 2017-02-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000442367 SCV000600343 likely benign not specified 2017-03-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000442367 SCV000602723 benign not specified 2017-02-04 criteria provided, single submitter clinical testing
Invitae RCV000758818 SCV000635914 likely benign not provided 2018-12-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758818 SCV000887675 benign not provided 2019-08-02 criteria provided, single submitter clinical testing
Color RCV000162699 SCV000909294 likely benign Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000442367 SCV000916800 likely benign not specified 2018-09-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3699A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 5 donor site, three predict the variant strengthens a cryptic 5 donor site, and three predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 276994 control chromosomes, predominantly at a frequency of 0.00087 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. The variant, c.3699A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005). One abstract from Myriad Laboratories cites the variant as co-occurring with pathogenic mutations. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.

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