Submissions for variant NM_007294.4(BRCA1):c.2773A>C (p.Ile925Leu)

gnomAD frequency: 0.00013  dbSNP: rs4986847

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031070	SCV000244328	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000326
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085981	SCV000075980	benign	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001703432	SCV000209946	likely benign	not provided	2021-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16518693, 22753008, 21990134, 18951461, 24853695, 24728327, 24729269, 17719744, 15235020, 17924331, 18951446, 23056176, 10923033, 22516946, 16267036, 25011685, 15385441)
Ambry Genetics	RCV000162517	SCV000212911	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000031070	SCV000488507	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000475644	SCV000540985	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162517	SCV000688400	likely benign	Hereditary cancer-predisposing syndrome	2016-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120274	SCV000698978	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2773A>C (p.Ile925Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251016 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American 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 Syndrome (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.2773A>C has been reported in the literature in individuals affected with breast cancer and prostate cancer (example, Biunno_2014, Judkins_2005, Leongamornlert_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome (example, Easton_2007, Lindor_2012). At-least one co-occurrence with another pathogenic variant has been observed in our laboratory (BRCA1 c.1386delG, p.Thr464fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000162517	SCV002538157	likely benign	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120274	SCV004026783	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031070	SCV000053666	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-06-20	no assertion criteria provided	clinical testing
ITMI	RCV000120274	SCV000084426	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031070	SCV000144543	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353708	SCV000591411	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile925Leu variant was identified in 2 of 40118 proband chromosomes (frequency: 0.0002) from individuals or families with Breast and Ovarian Cancer in a Sudanese and other populations (Abkevich 2004, Biunno 2014).The variant was identified by our laboratory in 1 individual with ovarian cancer. The variant was also identified in dbSNP (ID: rs rs4986847, with a minor allele frequency of 0.0002 (1000 Genomes Project); NHLBI Exome Sequencing Project (Exome Variant Server) in 4 of 4406 African Americans and 0 of 8600 European Americans; Exome Aggregation Consortium (ExAC) database in 12 of 10402 Africans and 1 of 11564 Latino, and not found in European (Non-Finnish),East Asian, South Asian, European (Finnish) or other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, the ClinVar database (classified as a Likely Benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; as likely Benign by GeneDX; as uncertain significance by BIC; as Benign by Ambry Genitics; ITMI and Invitae did not provide a classification). In the BIC database it was identified 4X with unknown clinical importance, and UMD (2X as an unknown variant). The p.Ile925 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Ile925Leu variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
PreventionGenetics, part of Exact Sciences	RCV004554624	SCV004759220	benign	BRCA1-related disorder	2019-03-01	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).