ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1137T>G (p.Ile379Met) (rs56128296)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167819 SCV000075370 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000111560 SCV000154012 likely benign Breast-ovarian cancer, familial 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: 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 1 2014-11-03 criteria provided, single submitter clinical testing
Pathway Genomics RCV000111560 SCV000223753 likely benign Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120301 SCV000225010 benign not specified 2014-08-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120301 SCV000311785 likely benign not specified criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167819 SCV000494348 benign Hereditary breast and 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 Health, Inc RCV000131737 SCV000682938 benign Hereditary cancer-predisposing syndrome 2015-10-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656645 SCV000806891 likely benign not provided 2015-09-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656645 SCV001151337 likely benign not provided 2019-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286585 SCV001473184 benign none provided 2020-07-07 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 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

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