Submissions for variant NM_007294.4(BRCA1):c.4245A>G (p.Glu1415=)

gnomAD frequency: 0.00002  dbSNP: rs41293453

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112303	SCV000578431	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/).
Invitae	RCV001080470	SCV000076512	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163656	SCV000214226	likely benign	Hereditary cancer-predisposing syndrome	2014-11-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000586731	SCV000564741	likely benign	not provided	2020-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12955716, 10686936, 16267036, 25980754)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483384	SCV000699124	likely benign	not specified	2019-07-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000112303	SCV000785995	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586731	SCV000888914	likely benign	not provided	2023-09-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163656	SCV000902936	likely benign	Hereditary cancer-predisposing syndrome	2015-08-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112303	SCV001283850	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000163656	SCV002538278	likely benign	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003894899	SCV004722683	likely benign	BRCA1-related condition	2019-07-30	criteria provided, single submitter	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112303	SCV000145039	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2000-01-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353593	SCV000591500	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1415Glu variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals; the authors call this variant a polymorphism (Diez 2003).The variant was also identified in dbSNP (ID: rs41293453) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), the ClinVar database (classified as an uncertain significance variant by the BIC), the BIC database (3X with unknown clinical importance), and UMD (1X as an unclassified variant).The variant was identified by the Exome Variant Server project in 3 of 13006 European American and African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Glu1415Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. Thus, this variant is classified as predicted benign.