ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.346C>T (p.His116Tyr)

gnomAD frequency: 0.00029  dbSNP: rs144856889
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131018 SCV000185944 likely benign Hereditary cancer-predisposing syndrome 2019-03-29 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.
GeneDx RCV000590105 SCV000209832 likely benign not provided 2021-07-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23056176, 26350354, 26787654, 27720647, 28873162, 28726808, 28135145)
Invitae RCV000205245 SCV000261522 likely benign Familial cancer of breast 2024-01-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855574 SCV000696773 benign not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: BARD1 c.346C>T (p.His116Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 282296 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.346C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, Colorectal Cancer, and pancreatic ductal adenocarcinoma (Lee_2015, Mu_2016, Tung_2015, Young_2016, Yurgelun_2017, Chaffee_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Lee_2015). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000205245 SCV000786359 uncertain significance Familial cancer of breast 2018-04-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131018 SCV000910697 likely benign Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing
Mendelics RCV000205245 SCV001136200 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000205245 SCV001299106 uncertain significance Familial cancer of breast 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4 RCV000131018 SCV002529613 likely benign Hereditary cancer-predisposing syndrome 2020-12-30 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000205245 SCV004019257 likely benign Familial cancer of breast 2023-02-24 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000855574 SCV004024869 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357830 SCV001553417 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.His116Tyr variant was identified in 1 of 604 proband chromosomes (frequency: 0.002) from individuals with pancreatic cancer (Chaffee 2018). The variant was identified in dbSNP (rs144856889) as “with other allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Integrated Genetics and Color; and as uncertain significance by Counsyl and GeneDx). The variant was identified in control databases in 88 of 282,296 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 42 of 25,062 chromosomes (freq: 0.002), Other in 3 of 7196 chromosomes (freq: 0.0004), and European in 42 of 128,918 chromosomes (freq: 0.0003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian or South Asian populations. In vitro expression of the variant did not alter BARD1 protein levels and there was no observed effect on homology directed repair activity (Lee 2015). The p.His116 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.