ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3748G>A (p.Glu1250Lys) (rs28897686)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112170 SCV000244348 benign Breast-ovarian cancer, familial 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 = 0.000000204
Invitae RCV000167791 SCV000076323 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000120296 SCV000167297 benign not specified 2014-01-23 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 RCV000162713 SCV000213174 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.
Counsyl RCV000112170 SCV000221124 benign Breast-ovarian cancer, familial 1 2015-02-06 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167791 SCV000494424 benign Hereditary breast and ovarian cancer syndrome 2015-10-26 criteria provided, single submitter clinical testing Variant Summary: c.3748G>A is a missense mutation that occurs at a non-conserved position, resulting in a change from medium size and acidic (E) to large size and basic (K) residue, and 3/4 in silico tools predict a benign outcome (SNPs&Go not captured here due to low reliability index). A heatmap of the unsupervised cluster analysis of several assays carried out by Loke et al 2015, showed that this missense variant clusters with WT BRCA1, Bouwman et al 2013 showed that the E1250K mutant protein behaves similarly to WT in a cisplatin (anticancer drug) sensitivity assay, and other studies have shown that it does not alter splicing and the protein is expressed at normal levels (Anczukow et al 2008). Lindor_2012 and Pavlicek_2004 predict that the variant is neutral based on in silico prediction models.The observed allele frequency in controls is 39/127500 (1/3269; 0.03%), which is lower than the maximal expected allele frequency of 1/1000 for a pathogenic BRCA1 variant. However, UMD cites a pathogenic BRCA2 co-occurrence in 1 individual, and BIC cites the variant to co-occur with pathogenic BRCA1 co-occurrences in 2 individuals (p.Tyr1563Ter and p.Trp1508Ter; also cited in Tavtigian et al 2006) and a BRCA2 pathogenic co-occurrence (p.Lys936_Gln937?fs) in 1 individual. Further more, in one HBOC family, the variant of interest did not co-segregate with disease (Jara_BRCA1_Biol Res_2004). These numerous pathogenic co-occurrences and lack of co-segregation with disease are a strong indication of a benign outcome for this missense BRCA1 variant. Additionally, numerous reputable databases and clinical diagnostic labs have classified this variant as benign. Taken together, this missense BRCA1 mutation is a normal variant and has been classified as benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120296 SCV000538442 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 30/66732 European; ClinVar: 6 B/LB
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000162713 SCV000679699 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162713 SCV000683128 likely benign Hereditary cancer-predisposing syndrome 2014-12-13 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000112170 SCV000744627 benign Breast-ovarian cancer, familial 1 2017-03-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120296 SCV000806940 benign not specified 2017-11-20 criteria provided, single submitter clinical testing
Mendelics RCV000112170 SCV001140544 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112170 SCV001284944 likely benign Breast-ovarian cancer, familial 1 2018-08-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289592 SCV001477554 benign none provided 2020-03-05 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001662159 SCV001878332 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
ITMI RCV000120296 SCV000084448 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000112170 SCV000144857 benign Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148379 SCV000190077 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353803 SCV000591469 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu1250Lys variant was identified in at least 6 of 111702 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer and was present in 2 of 2508 control chromosomes (frequency: 0.001) from healthy individuals (Diez 2003, Grudinina 2005, Jara 2004, Judkins 2005, Osorio 2007, Salazar 2006). The variant was also identified in dbSNP (ID: rs28897686) “With pathogenic allele”, HGMD, LOVD, the BIC database (20X with no clinical importance), and UMD (14X as a neutral variant). In UMD, one sample found the variant co-occurring with a pathogenic mutation in BRCA2 (c.368_372delAAATG (p.Lys123ArgfsX5)), increasing the likelihood that the p.Glu1250Lys variant may not have clinical importance. The p.Glu1250 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact of the p.Glu1250Lys variant to the protein; this information is not very predictive of pathogenicity. The variant was listed in the NHLBI Exome Sequencing Project in 4 of 130006 alleles (frequency: 0.0003), increasing the likelihood that this may represent a low frequency benign variant. One study identified the variant co-occurring in trans with two different deleterious BRCA1 mutations, increasing the likelihood that the variant does not have clinical significance (Judkins 2005). In addition, one functional study and three in silico studies all found the variant to be neutral (Bouwman 2013, Abkevich 2004 15235020, Lindor 2012, Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112170 SCV000733620 benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735477 SCV000863614 benign Breast and/or ovarian cancer 2013-11-07 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000120296 SCV001799534 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120296 SCV001906200 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120296 SCV001957357 benign not specified no assertion criteria provided clinical testing

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