Submissions for variant NM_007294.4(BRCA1):c.43A>C (p.Ile15Leu)

gnomAD frequency: 0.00001  dbSNP: rs80357031

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132290	SCV000187375	likely benign	Hereditary cancer-predisposing syndrome	2018-08-31	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.
Counsyl	RCV000111636	SCV000785185	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132290	SCV000911280	likely benign	Hereditary cancer-predisposing syndrome	2017-10-10	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248950	SCV001422730	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Ile15Leu variant in BRCA1 has been reported in 3 Iranian individual with breast cancer, 1 Algerian individual with breast or ovarian cancer, 1 individual with pancreatic cancer, and 1 individual in a genetic testing cohort (PMID: 21918854, 22684231, 27449771, 15235020), and has been identified in 0.01148% (1/8712) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80357031). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease also present in the general population. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely benign variant in ClinVar (Variation ID: 55192). In vitro functional studies provide some evidence that the p.Ile15Leu variant may not impact protein function (PMID: 16403807). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Isoleucine (Ile) at position 15 is not highly conserved in mammals and evolutionary distant species, and 47 species carry a Leucine (Leu), raising the possibility at this position may be tolerated. Two additional variants, resulting in a different amino acid change at the same position, p.Ile15Thr and p.Ile15Leu, have been reported as a VUS in association with disease in ClinVar (Variation ID: 55217, 55192). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, BS3_Supporting (Richards 2015).
Baylor Genetics	RCV000111636	SCV001482786	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-03-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001348288	SCV001542585	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111636	SCV000144119	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111636	SCV001237730	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro