ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2428A>T (p.Asn810Tyr) (rs28897682)

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Total submissions: 12
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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) RCV000077518 SCV000244318 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 = 0.000000000000233
Invitae RCV000167805 SCV000075849 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000047836 SCV000167278 benign not specified 2014-02-26 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 RCV000162593 SCV000213011 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.
Counsyl RCV000077518 SCV000220977 likely benign Breast-ovarian cancer, familial 1 2014-12-22 criteria provided, single submitter literature only
Color Health, Inc RCV000162593 SCV000683035 benign Hereditary cancer-predisposing syndrome 2015-12-30 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000047836 SCV000806915 benign not specified 2017-10-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286505 SCV001473091 likely benign none provided 2020-01-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077518 SCV000109319 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077518 SCV000144433 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000077518 SCV000187726 benign Breast-ovarian cancer, familial 1 2014-12-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356676 SCV001551911 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.Asn810Tyr variant was identified in 1 of 200 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Peixoto 2006,). The variant was identified in dbSNP (rs28897682) as “with benign allele”, ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics, Color and 4 other submitters; as likely benign by Counsyl; and as uncertain significance by BIC), LOVD 3.0 (observed 15x) and UMD-LSDB (observed 19x). The variant was identified in control databases in 17 of 245,294 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5 of 33,562 chromosomes (freq: 0.0001), European in 12 of 111,138 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was observed in trans with a co-occurring pathogenic BRCA1 variant (c.3748 G>T, p.Glu1250*; Judkins 2005). Additionally, the variant was reported in the UMD-LSDB database as co-occurring with a pathogenic BRCA1 variant (c.2359dup, p.Glu787Glyfs*3). In a complementation assay in BRCA1-deficient mouse embryonic stem cells, the variant was demonstrated to have no observed effect on cell proliferation and sensitivity to cisplatin indicating the variant protein activity was sufficient to complement the BRCA1 null cells (Bouwman 2013). The p.Asn810 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.

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