Submissions for variant NM_007294.4(BRCA1):c.1617G>A (p.Thr539=)

gnomAD frequency: 0.00006  dbSNP: rs372002119

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495451	SCV000578339	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000164403	SCV000215039	likely benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001081433	SCV000289747	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588370	SCV000698879	likely benign	not provided	2016-06-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1617G>A (p.Thr539Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant along with 3/5 slice site tools predicting the variant not to have an impact on normal splicing. This variant was found in 6/121200 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in HBOC patients, however without strong evidence for pathogenicity such as co-segregation information. The variant was reported to co-occur with a potentially pathogenic BRCA1 variant c.2429delA (p.Asn810ThrfsX5) in one individual indicating a benign nature. One clinical diagnostic laboratory classified this variant as Likely benign via ClinVar (without evidence to independently evaluate). Taken together, this variant is classified as Likely Benign.
GeneDx	RCV000588370	SCV000731115	likely benign	not provided	2020-02-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11013445, 25556971, 12457999, 28288110)
Counsyl	RCV000495451	SCV000786371	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000503015	SCV000887629	benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164403	SCV000909372	likely benign	Hereditary cancer-predisposing syndrome	2017-12-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000495451	SCV001287421	uncertain significance	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000503015	SCV002068316	likely benign	not specified	2018-01-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000503015	SCV004026799	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892117	SCV004716323	likely benign	BRCA1-related condition	2022-05-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588370	SCV000591344	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Thr539Thr variant was identified in dbSNP (rs372002119) and ClinVar (Likely benign, reviewed by expert panel. Classified as likely benign by: ENIGMA, Counsyl, Color, Amrby, Invitae, Integrated Genetics, GeneDx, Quest Diagnostics. Classified as benign by COGR, VUS by Illumina). The variant was reported to co-occur with a potentially pathogenic BRCA1 variant c.2429delA (p.Asn810ThrfsX5) in one individual, providing evidence in support of a benign classification (SCV000698879.1). The variant was identified in control databases in 12 of 282266 chromosomes (0 homozygous) at a frequency of 0.00004251 and was observed at the highest frequency in the African population in 2 of 24940 chromosomes (freq: 0.00008019) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Thr539Thr variant is a synonymous variant at a poorly conserved nucleotide. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588370	SCV001741756	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000503015	SCV001906273	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588370	SCV001932104	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588370	SCV001959404	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588370	SCV001975432	likely benign	not provided		no assertion criteria provided	clinical testing