ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5158A>G (p.Thr1720Ala) (rs56195342)

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Total submissions: 13
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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) RCV000077605 SCV000244390 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 = 0.000000000000344
Invitae RCV000203648 SCV000076849 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000175327 SCV000167319 benign not specified 2014-02-21 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 RCV000162823 SCV000213306 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000175327 SCV000226798 likely benign not specified 2015-03-10 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077605 SCV000743378 benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077605 SCV000744593 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162823 SCV000910646 benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Mendelics RCV000077605 SCV001140482 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077605 SCV000109408 uncertain significance Breast-ovarian cancer, familial 1 2008-11-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077605 SCV000145365 uncertain significance Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353742 SCV000591588 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr1720Ala variant was identified in 5 of 1840 proband chromosomes (frequency: 0.003) from individuals or families with hereditary breast and ovarian cancer and was not identified in 192 control chromosomes from healthy individuals (Diez 2003, McKean-Cowdin 2005, Osorio 2002). The variant was identified in dbSNP (rs56195342) as “with other allele”, ClinVar (classified as benign by Invitae, Color, GeneDx, Ambryu Genetics and 3 other submitters, likely benign by Eurofins and Sinai Health System and uncertain significance by BIC and SCRP), LOVD 3.0 (observed 27x) and UMD-LSDB (observed 18x). The variant was identified in control databases in 48 of 282,388 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 34 of 35,422 chromosomes (freq: 0.001), Other in 3 of 7200 chromosomes (freq: 0.0004), European in 10 of 129,006 chromosomes (freq: 0.00008), African in 1 of 24,958 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. In UMD-LSDB, the variant was observed in samples with co-occurring pathogenic BRCA1 (c.3481_3491del, p.Glu1161Phefs*3) and BRCA2 (c.5706_5712delins10, p.Asp1902Glufs*7 and c.1440_1441delCA, p.Ile481Serfs*32) variants. In multiple studies, the variant was demonstrated to have no effect on BRCA1 protein stability, binding, transactivation activity and response to cisplatin (Williams 2003, Phelan 2005, Carvalho 2007, Lee 2010, Bouwman 2013). The p.Thr1720 residue is not conserved in mammals and 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 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.
Brotman Baty Institute,University of Washington RCV000077605 SCV001242280 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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