Submissions for variant NM_007294.4(BRCA1):c.1137T>G (p.Ile379Met)

gnomAD frequency: 0.00158  dbSNP: rs56128296

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167819	SCV000075370	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000111560	SCV000154012	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-21	criteria provided, single submitter	literature only
GeneDx	RCV000120301	SCV000167239	benign	not specified	2014-01-24	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.
Ambry Genetics	RCV000131737	SCV000186778	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111560	SCV000195890	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000111560	SCV000223753	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120301	SCV000225010	benign	not specified	2014-08-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554647	SCV000311785	benign	BRCA1-related disorder	2020-10-30	criteria provided, single submitter	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167819	SCV000494348	benign	Hereditary breast ovarian cancer syndrome	2014-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000462490	SCV000540969	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120301	SCV000593662	benign	not specified	2019-06-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131737	SCV000682938	benign	Hereditary cancer-predisposing syndrome	2015-10-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656645	SCV001151337	likely benign	not provided	2019-01-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656645	SCV001473184	benign	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131737	SCV002537998	benign	Hereditary cancer-predisposing syndrome	2020-07-02	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490618	SCV002798139	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-10	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167819	SCV002819214	benign	Hereditary breast ovarian cancer syndrome	2022-11-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492375	SCV004240205	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000111560	SCV004818366	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
ITMI	RCV000120301	SCV000084453	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111560	SCV000144023	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148386	SCV000190084	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353986	SCV000591318	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile379Met variant was identified in 3 of 634 proband chromosomes (frequency: 0.005) from individuals or families with Breast cancer and was present in 2 of 192 control chromosomes (frequency: 0.01) from healthy individuals (Fackenthal, 2005; McKean-Cowdin, 2005). The variant was also identified in dbSNP (ID: rs56128296) “With other allele”, with a minor allele frequency of 0.002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, ClinVar database (with conflicting data from submitters including BIC (Benign), Counsyl (likely Benign), Invitae and ITMI (not provided), and UMD (10X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.815_824dup (p.Thr276AlafsX14)), increasing the likelihood that the p.Ile379Met variant does not have clinical significance. In the exome Variant Server project the variant was identified in 28 of 4406 African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Studies suggest this variant is common in African populations and does not have an effect on protein function (McKean-Cowdin, 2005). The p.Ile379 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Functional assays performed by Millot (2012) indicate no reduction in expression when this variant is present. Abkevich (2004) report this variant as having a Grantham score of 10 suggesting little to no effect on the protein. In summary, based on the above information,this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656645	SCV000778772	benign	not provided	2017-08-02	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131737	SCV000805226	likely benign	Hereditary cancer-predisposing syndrome	2018-04-27	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656645	SCV001951406	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656645	SCV001968842	likely benign	not provided		no assertion criteria provided	clinical testing