ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2634A>G (p.Ala878=) (rs730881451)

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Total submissions: 9
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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) RCV000495552 SCV000578242 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/).
GeneDx RCV000159876 SCV000209943 benign not specified 2014-08-15 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 RCV000163881 SCV000214471 likely benign Hereditary cancer-predisposing syndrome 2014-06-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign
Invitae RCV001085410 SCV000259984 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163881 SCV000683051 likely benign Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679689 SCV000806924 likely benign not provided 2017-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679689 SCV000887650 benign not provided 2018-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159876 SCV000916728 likely benign not specified 2018-05-31 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2634A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.9e-05 in 245860 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8.9e-05 vs 0.001), allowing no conclusion about variant significance. c.2634A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports experimental evidence evaluating an impact on protein function, but does not provide convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000679689 SCV000591399 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.Ala878= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs730881451) as “With other allele”, ClinVar (as likely benign reviewed by expert panel), Clinvitae, GeneInsight-COGR (as likely benign by COGR consensus), LOVD 3.0 (4x), and UMD-LSDB (5x as UV) databases. The variant was identified in control databases in 22 of 245860 chromosomes at a frequency of 0.000089 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 13 of 33568 chromosomes (freq: 0.000387), South Asian in 5 of 30774 chromosomes (freq: 0.000163), Ashkenazi Jewish in 1 of 9848 chromosomes (freq: 0.000102), and European (Non-Finnish) in 3 of 111526 chromosomes (freq: 0.000027), while the variant was not observed in the African, East Asian, European (Finnish), and Other populations. The p.Ala878= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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