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

gnomAD frequency: 0.00150  dbSNP: rs56158747

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195320	SCV000076641	benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000679699	SCV000167309	benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15350310, 24055113, 25637381, 22505045, 8776600, 10811118, 26689913, 27153395, 26332594, 28781887, 16267036, 15726418, 17308087, 22811390, 30765603, 33087888)
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: seen in unaffected individuals, 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, susceptibility to, 1	2014-04-26	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	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 ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131708	SCV000683205	likely benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679699	SCV000806957	likely benign	not provided	2016-10-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679699	SCV000885081	benign	not provided	2023-09-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000077584	SCV001140515	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077584	SCV001280756	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195320	SCV002025929	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000174915	SCV002065792	likely benign	not specified	2021-02-26	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000195320	SCV002515216	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131708	SCV002537771	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272046	SCV002556859	likely benign	Familial cancer of breast	2020-08-11	criteria provided, single submitter	clinical testing	The BRCA1 c.4682C>T variant is classified as Likely Benign (BS2, BP6)
All of Us Research Program, National Institutes of Health	RCV004804005	SCV004817641	likely benign	BRCA1-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077584	SCV000109387	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-08-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077584	SCV000145158	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679699	SCV001951333	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679699	SCV001975965	uncertain significance	not provided		no assertion criteria provided	clinical testing