ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1911T>C (p.Thr637=) (rs62625305)

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Total submissions: 13
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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) RCV000111731 SCV000578223 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV001083820 SCV000075649 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000168494 SCV000167245 benign not specified 2014-02-05 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000111731 SCV000195896 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162772 SCV000213249 likely benign Hereditary cancer-predisposing syndrome 2014-07-01 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000168494 SCV000219212 benign not specified 2017-01-18 criteria provided, single submitter clinical testing
Counsyl RCV000111731 SCV000220247 likely benign Breast-ovarian cancer, familial 1 2014-04-15 criteria provided, single submitter literature only
Color Health, Inc RCV000162772 SCV000683001 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679685 SCV000806903 likely benign not provided 2017-06-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168494 SCV000918678 likely benign not specified 2019-02-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1911T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. In vitro splicing, assessed by mini-gene assay, shows that the variant does not impact BRCA1 splicing (Anczukow_2008). The variant allele was found at a frequency of 0.0001 in 277214 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00022 vs 0.001), allowing no conclusion about variant significance. c.1911T>C has been reported in the literature in individuals affected or at risk for Hereditary Breast and Ovarian Cancer (Zanella_2017, Caminsky_2016, DArgenio_2015, Borg_2010, Anczukow_2008, Judkins_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in the UMD database (BRCA1 c.514C>T, p.Gln172X; BRCA2 c.6033_6034delTT, p.Ser2012GlnfsX5), providing supporting evidence for a benign role. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (3x) and twice as benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287246 SCV001473917 likely benign none provided 2019-09-10 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111731 SCV000144245 uncertain significance Breast-ovarian cancer, familial 1 2010-12-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168494 SCV000591355 benign not specified no assertion criteria provided clinical testing This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction and is reported as a polymorphism in one publication (Judkins 2005). In addition, it reported to co-occur with a second pathogenic variant in 2 individuals in the UMD database.

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