ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4682C>T (p.Thr1561Ile) (rs56158747)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195320 SCV000076641 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000174915 SCV000167309 benign not specified 2014-01-14 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 RCV000131708 SCV000186746 benign Hereditary cancer-predisposing syndrome 2014-06-24 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 RCV000077584 SCV000220274 benign Breast-ovarian cancer, familial 1 2014-04-26 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174915 SCV000226315 likely benign not specified 2016-01-11 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000195320 SCV000576439 likely benign Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131708 SCV000683205 likely benign Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679699 SCV000806957 likely benign not provided 2016-10-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283443 SCV000885081 benign none provided 2019-09-24 criteria provided, single submitter clinical testing
Mendelics RCV000077584 SCV001140515 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000077584 SCV001280756 likely benign Breast-ovarian cancer, familial 1 2017-04-28 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000077584 SCV000109387 benign Breast-ovarian cancer, familial 1 2008-08-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077584 SCV000145158 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148378 SCV000190076 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353900 SCV000591536 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr1561Ile variant was identified in 3 of 806 proband chromosomes (frequency: 0.004) from individuals with breast or ovarian cancer and was absent in 432 control chromosomes from these studies (Durocher 1996, McKean-Cowdin 2005). The variant was also identified in at least 20 other patients from a data set 55630 patients undergoing clinical BRCA1 mutation screening (Judkins 2005). The p.Thr1561Ile variant was identified in HGMD, LOVD, the BIC database (26X with unknown clinical importance), and UMD (4X as a neutral variant). In UMD the variant was listed once as co-occurring with a known pathogenic mutation in BRCA1 (c.-200_80del (p.Met1SerfsX13)), and Judkins (2005) identified the variant in trans with a different pathogenic BRCA1 mutation (p.Cys64Tyr), increasing the likelihood that the p.Thr1561Ile variant does not have clinical importance. The variant was listed in dbSNP (ID: rs56158747) with a minor allele frequency of 0.002 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project with a frequency of 0.005 in African American alleles, increasing the likelihood that this is a low frequency benign polymorphism in certain populations of origin. This residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Two functional studies using a yeast transcription activation assay found that the variant displayed wild-type activity (Carvalho 2007, Hayes 2000). In addition, Durocher (1996) found this variant in the germline but absent in a breast tumour from a patient, suggesting a benign effect of the variant on protein function. 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 predicted benign.
True Health Diagnostics RCV000131708 SCV000787904 likely benign Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing

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