ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1105G>A (p.Asp369Asn) (rs56056711)

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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) RCV000030971 SCV000244294 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000568
Invitae RCV000047341 SCV000075354 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162972 SCV000213460 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV001703430 SCV000515314 likely benign not provided 2020-11-13 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 21990134, 15235020, 22753008, 16677609)
Counsyl RCV000030971 SCV000785357 benign Breast-ovarian cancer, familial 1 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162972 SCV000903485 benign Hereditary cancer-predisposing syndrome 2016-06-19 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659738 SCV001878172 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000030971 SCV000053562 likely benign Breast-ovarian cancer, familial 1 2012-01-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030971 SCV000144010 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735458 SCV000863595 pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358186 SCV001553857 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp369Asn variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs56056711) as with other allele; in the ClinVar and Clinvitae databases as benign by ENIGMA, Ambry Genetics; as likely benign by GeneDx, Invitae,Sharing Clinical Report Project; and as uncertain significance by CHEO Genetics Diagnostic Laboratory and Breast Cancer Information Core. The variant was also identified in the LOVD 3.0 database 3X as predicted neutral, BIC Database 2X as clinical importance unknown, and in the ARUP Laboratories database as not pathogenic or of no clinical significance. The variant was identified in control databases in 4 of 245866 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 4 of 111388 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In one study, authors utilized amino acid conservation and residue properties to classify missense variants and found the p.Asp369Asn variant to be neutral or of little clinical significance (Abkevich 2004). The p.Asp369Asn residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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