ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4347A>G (p.Thr1449=) (rs80356840)

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Total submissions: 11
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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) RCV000112321 SCV000578185 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;
Invitae RCV001082944 SCV000076544 benign Hereditary breast and ovarian cancer syndrome 2020-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166538 SCV000217339 likely benign Hereditary cancer-predisposing syndrome 2014-10-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign
GeneDx RCV000437448 SCV000512309 likely benign not specified 2017-10-02 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 RCV000166538 SCV000683172 likely benign Hereditary cancer-predisposing syndrome 2015-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000437448 SCV000699134 benign not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4347A>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 observed variant frequency within East Asian control individuals in the gnomAD database (0.001) is close to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0087 (HGVD), strongly suggesting a benign role for the variant. c.4347A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Han 2006, Judkins 2005, Kim 2006, Lee 2003, Hwang 2017). However, in several of these publications the authors listed the variant of interest as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000112321 SCV000785875 likely benign Breast-ovarian cancer, familial 1 2017-12-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048531 SCV001133582 benign not provided 2019-05-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112321 SCV001283848 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112321 SCV000145064 benign Breast-ovarian cancer, familial 1 2004-12-27 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355721 SCV001550678 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr1449= variant was identified in 7 of 3724 proband chromosomes (frequency: 0.002) from Korean and Malaysian individuals or families with breast cancer, sporadic or unselected for family history, and was not identified in 334 control chromosomes from healthy individuals (Han 2006, Kim 2006, Lee 2003). The variant was also identified in the following databases: dbSNP (ID: rs80356840) as “With other allele”, in ClinVar (likely benign, reviewed by an expert panel 2017; submitters: benign by BIC, likely benign by ENIGMA, Invitae, Ambry Genetics and GeneDx), in Clinvitae (4x), and BIC Database (1x, with no clinical importance, classification pending), and was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 22 of 277016 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6464 chromosomes (freq: 0.0002), East Asian in 20 of 18866 chromosomes (freq: 0.001), and South Asian in 1 of 30758 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, and Finnish populations. The p.Thr1449= 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. The variant occurs 11 nucleotides from the 3’ end of exon 11 and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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