ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3823A>G (p.Ile1275Val) (rs80357280)

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Total submissions: 17
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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) RCV000031130 SCV001161512 benign Breast-ovarian cancer, familial 1 2019-06-18 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 = 4.02E-06
Invitae RCV000195318 SCV000076359 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000120279 SCV000209962 likely benign not specified 2018-01-19 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 RCV000162522 SCV000212917 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000034745 SCV000224999 uncertain significance not provided 2015-04-22 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000195318 SCV000258061 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-02-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031130 SCV000743399 benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031130 SCV000744622 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162522 SCV000910633 benign Hereditary cancer-predisposing syndrome 2015-11-30 criteria provided, single submitter clinical testing
Mendelics RCV000031130 SCV001140541 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120279 SCV001158790 likely benign not specified 2019-01-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034745 SCV001247352 likely benign not provided 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120279 SCV001338472 likely benign not specified 2020-04-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3823A>G (p.Ile1275Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251142 control chromosomes, predominantly at a frequency of 0.0009 within the Latino subpopulation in the gnomAD database. This frequency is similar to the estimated maximum allele frequency expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.0009 vs 0.001), suggesting that this variant could be a rare benign polymorphism found predominantly in populations of Latino origin. c.3823A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, however without strong evidence for causality (such as co-segregation data; examples- Judkins_2005, Spearman_2008, Caux-Moncoutier_2009, Borg_2010, Lu_2012, Solano_2013, Dean_2015, Fernandes_2016, Kraus_2017, Brianese_2018, Germani_2018, Diaz-Zabala_2018, Zuntini_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8364G>A, p.Trp2788X, UMD Database and BRCA2 c.3922G>T, p.Glu1308X, BIC), providing supporting evidence for a benign role. Several publications investigating the variant effect in-vitro reported no impact on splicing or allelic imbalance (Anczukow_2008, Caux-Montcoutier_2009), however to our knowledge, no experimental evidence evaluating an impact on protein function has been reported. A total of ten other ClinVar submitters (evaluation after 2014) have asssessed the variant for clinical significance and have cited the variant as benign (n=5, including one expert panel), likely benign (n=3), and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034745 SCV000043163 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031130 SCV000053729 benign Breast-ovarian cancer, familial 1 2008-11-12 no assertion criteria provided clinical testing
ITMI RCV000120279 SCV000084431 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000031130 SCV000144888 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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