ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1418A>G (p.Asn473Ser) (rs80357057)

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Total submissions: 8
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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) RCV000111612 SCV000244301 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 = 0.00000337
Invitae RCV000047470 SCV000075483 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000435379 SCV000512286 likely benign not specified 2016-03-02 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.
Color Health, Inc RCV000584571 SCV000688337 likely benign Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000111612 SCV000785609 benign Breast-ovarian cancer, familial 1 2017-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000584571 SCV001171761 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111612 SCV000144088 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354245 SCV001548808 uncertain significance not provided no assertion criteria provided clinical testing The BRCA1 p.Asn473Ser variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Lindor 2012, van der Stoep 2009). Studies by Easton 2007 and Lindor 2012 predict this variant has a low probability of being deleterious. The variant was identified in the following databases: dbSNP (ID: rs80357057) as "With Uncertain significance, other allele", ClinVar (1x benign, reviewed by expert panel ENIGMA, 2x likely benign, 2x uncertain significance), Clinvitae, LOVD 3.0 (4x, predicted neutral), BIC Database (2x), and ARUP Laboratories (Not pathogenic or of no clinical significance). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4 of 277024 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Finnish in 1 of 25778 chromosomes (freq: 0.00004), and South Asian in 2 of 30778 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Latino, European, Ashkenazi Jewish, or East Asian populations. The p.Asn473 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. This variant is classified as a variant of uncertain significance.

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