ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3640G>A (p.Glu1214Lys) (rs80356923)

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Total submissions: 14
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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) RCV000112142 SCV000244344 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 = 0.000000000689
Invitae RCV001080705 SCV000076279 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162552 SCV000212962 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.
GeneDx RCV000433388 SCV000515872 benign not specified 2017-09-11 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.
Color Health, Inc RCV000162552 SCV000683118 likely benign Hereditary cancer-predisposing syndrome 2015-06-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590363 SCV000699049 likely benign not provided 2016-03-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3640G>A variant affects a conserved nucleotide, resulting in amino acid change from a medium size and acidic Glu to a large size and basic Lys. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). Comparative evolutionary approach for classifying the variant using mammalian BRCA1 sequences as performed by Burk-Herrick et al 2005 shows that this variant has low oncogenic score. Large multifactorial likelihood-ratio model study that included cosegregation, co-occurrence and logistic regression analyses shows that this variant has high odds in favor of benign effect (Easton et al 2007). This genetic and probability based study is particularly convincing for determination of pathogenicity. Similarly, in another multifactorial probability model study, it was shown to have very low odds in favor of causality (Lindor et al 2012). Functional studies at the protein level have not been carried out; however, a minigene assay suggests that the variant does not affect normal splicing (Anczukow et al 2008). This variant was found in 10/121208 control chromosomes at a frequency of 0.0000825, which does not exceed the maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The highest allele frequency was in Latinos from the ExAC project (0.00034698), which is 2-3 fold less than the maximal expected BRCA1 pathogenic allele frequency. These data still do suggests that this variant could be a rare polymorphism in general population. In addition, more importantly, this variant did not segregate with prostate cancer in at least one family -- while it was found in at least one affected member, there was also at least one affected member who did not carry it (Zuhlke et al 2004). Furthermore, the variant was also found to co-occur with a pathogenic BRCA2 variant c.6833_6837delTCTTA, supporting a likely benign outcome. Multiple clinical laboratories/reputable databases classified this variant as benign. Taken together this variant has currently been classified as likely benign until additional data are available (i.e. functional, co-occurrence, and/or co-segregation data).
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162552 SCV000803148 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590363 SCV000806937 likely benign not provided 2017-02-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000433388 SCV000966375 likely benign not specified 2018-05-07 criteria provided, single submitter clinical testing p.Glu1214Lys in exon 10A of BRCA1: This variant is classified as likely benign b ecause it did not segregate with disease in one family and since it has been ide ntified in 0.03% (12/3438)) of Latino chromosomes by the Genome Aggregation Data base (gnomAD,; dbSNP rs80356923). In addition, this variant was classified as benign on Aug 10, 2015 by the ClinGen-approved (E NIGMA) expert panel (ClinVar 54948). Computational prediction tools and conserva tion analysis suggest that the p.Glu1214Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG /AMP Criteria applied: BS4, BP4.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000433388 SCV001156832 likely benign not specified 2018-07-31 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112142 SCV000144819 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000433388 SCV000587325 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353446 SCV000591458 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu1214Lys variant was identified in one individual with ovarian cancer and one family with hereditary prostate cancer; however, control chromosomes from healthy individuals were not included in these studies (Akbari 2011, Zuhlke 2004). The variant was also identified in dbSNP (ID: rs80356923) ‚ With untested allele‚Äù, LOVD, COSMIC, UMD (8X as a neutral variant), and the BIC database (9X with unknown clinical importance). This residue is conserved in mammals but not across lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One in silico study by Tram (2013) suggests that the variant may affect protein binding to neighbouring nucleotides; however, two other in silico studies using a multifactorial likelihood-ratio model predict this variant to be neutral or likely not pathogenic (Easton 2007, Lindor 2012). However, Myriad has found this variant in trans with a known deleterious mutation and classify it as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000590363 SCV000778744 likely benign not provided 2017-01-03 no assertion criteria provided clinical testing

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