ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1347A>G (p.Gln449=) (rs373257776)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212128 SCV000209820 benign not specified 2014-07-07 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 RCV000159796 SCV000213158 likely benign Hereditary cancer-predisposing syndrome 2014-09-10 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.
Invitae RCV000199945 SCV000254568 benign Familial cancer of breast 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000159796 SCV000682685 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212128 SCV000696739 likely benign not specified 2019-08-21 criteria provided, single submitter clinical testing
Mendelics RCV000199945 SCV000837964 likely benign Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000858081 SCV001153293 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Lab. Molecular Oncology,VUB, Free University of Brussels RCV000678224 SCV000804243 uncertain significance Triple-Negative Breast Cancer Finding 2015-02-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355909 SCV001550928 uncertain significance Familial ovarian cancer no assertion criteria provided clinical testing The BARD1 p.Gln449= variant was identified in 2 of 2596 proband chromosomes (frequency: 0.0008) from individuals or families with triple negative breast cancer and individuals tested for Lynch Syndrome testing and was not identified in 490 control chromosomes from healthy individuals (De Brakeleer_2016_26010302, Yurgelun_2015_25980754). The variant was also identified in the following databases: dbSNP (ID: rs373257776) as “With Likely benign allele”, ClinVar Clinvitae (1x as benign by GeneDx, 2x as likely benign by Ambry Genetics and Invitae). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 60 of 277060 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24030 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.00015), Latino in 10 of 34378 chromosomes (freq: 0.0003), European Non-Finnish in 48 of 126608 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gln449= variant is not expected to have clinical significance because it does not result in a change of amino acid. This variant occurs outside of the splicing consensus sequence but 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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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