ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.722C>G (p.Ser241Cys) (rs3738885)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212122 SCV000167164 benign not specified 2014-03-21 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 RCV000131461 SCV000186445 benign Hereditary cancer-predisposing syndrome 2015-01-20 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000206369 SCV000260648 benign Familial cancer of breast 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000206369 SCV000488723 likely benign Familial cancer of breast 2016-06-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212122 SCV000600204 benign not specified 2017-01-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131461 SCV000682810 benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Mendelics RCV000206369 SCV000837977 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212122 SCV000920363 benign not specified 2017-09-07 criteria provided, single submitter clinical testing Variant summary: The BARD1 c.722C>G (p.Ser241Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of ExAC in 25/114604 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002784 (24/8622). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. A case-control study found this variant to not be significantly associated with breast cancer (Ishitobi_BARD1_2003). This variant was found in a pancreatic ductal adenocarcinoma patient with no strong evidence for causality (Ohmoto_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212122 SCV001160410 likely benign not specified 2019-03-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000206369 SCV001296630 benign Familial cancer of breast 2017-04-27 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357291 SCV001552717 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Ser241Cys variant was identified in 11 of 286 proband chromosomes (frequency: 0.04) from individuals or families with breast cancer and was present in 8 of 310 control chromosomes (frequency: 0.03) from healthy individuals (Ishitobi 2003). The variant was also identified in the following databases: dbSNP (ID: rs3738885) as With Uncertain significance, other allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics; classified as likely benign by Counsyl, QDNISJC clinical laboratory), Clinvitae, MutDB, Zhejiang Colon Cancer Database (2X). The variant was not identified in Cosmic, database. The variant was identified in control databases in 27 of 211500 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 4468 chromosomes (freq: 0.0002), East Asian in 26 of 15562 chromosomes (freq: 0.002); it was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. Although the p.Ser241 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 4 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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