Submissions for variant NM_007294.4(BRCA1):c.3699A>G (p.Lys1233=)

gnomAD frequency: 0.00002  dbSNP: rs368690455

Total submissions: 11

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, susceptibility to, 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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000758818	SCV000512301	likely benign	not provided	2019-11-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16267036)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758818	SCV000602723	likely benign	not provided	2024-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084864	SCV000635914	benign	Hereditary breast ovarian cancer syndrome	2025-01-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758818	SCV000887675	benign	not provided	2023-08-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162699	SCV000909294	likely benign	Hereditary cancer-predisposing syndrome	2017-12-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442367	SCV000916800	likely benign	not specified	2024-08-08	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: One predict the variant creates a cryptic 5' donor site. Two predict the variant strengthens the cryptic 5' donor site. One predict the variant no significant impact on splicing. However, this variant is almost 400 nucleotides away from the nearest canonical splice donor site, and these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251278 control chromosomes, predominantly at a frequency of 0.00087 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.001), allowing no conclusion about variant significance. c.3699A>G has been reported in the literature in individuals undertaking genetic testing for Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (example, Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 36451132). ClinVar contains an entry for this variant (Variation ID: 183855). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000495287	SCV004817766	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359400	SCV005915278	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Fanconi anemia, complementation group S	2022-05-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554720	SCV004715043	likely benign	BRCA1-related disorder	2020-11-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).