Submissions for variant NM_007294.4(BRCA1):c.1616C>T (p.Thr539Met)

gnomAD frequency: 0.00004  dbSNP: rs80357374

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111655	SCV001161488	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.000273
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225759	SCV000075555	benign	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000586975	SCV000209930	likely benign	not provided	2019-12-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12491499, 24728327, 15235020, 26535628, 25801821, 20167696, 27616075, 29297111, 30287823, 31131967, 31825140, 33087888)
Ambry Genetics	RCV000162708	SCV000213169	likely benign	Hereditary cancer-predisposing syndrome	2019-02-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000111655	SCV000488835	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-06-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586975	SCV000600259	likely benign	not provided	2020-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586975	SCV000698878	benign	not provided	2016-03-17	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interest causes a misense change involving a non-conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/120938 (1/10993), predominantly in the South Asian cohort, 9/16496 (1/1832), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications and databases, which indicate the variant to co-occur with pathogenic BRCA1 variants, c.1687C>T (p.Gln563X - classified as pathogenic by LCA) and c.5030_5033delCTAA (p.Thr1677IlefsX2 - classified as pathogenic by LCA) and 3 different BRCA2 variants, c.2808_2811delACAA(p.Lys936_Gln937?fs) c.6037A>T (p.Lys2013Ter) and c.3975_3978dupTGCT (p.Ala1327fsX4), indicating a benign role. In addition, multiple reputable clinical laboratories cite the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000162708	SCV000910914	benign	Hereditary cancer-predisposing syndrome	2016-11-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170824	SCV001333442	likely benign	Breast and/or ovarian cancer	2023-06-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162708	SCV002538043	likely benign	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120282	SCV002551033	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120282	SCV004848653	likely benign	not specified	2022-05-20	criteria provided, single submitter	clinical testing	The p.Thr539Met variant in BRCA1 is classified as likely benign due to a lack of conservation across species. >20 mammals carry a Methionine at this position despite high nearby amino acid conservation. In addition, computational prediction tools predict that this variant does not impact the protein. It has been identified in 0.04% (13/30592) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Benign on June 18, 2019 by the ClinGen-approved ENIGMA expert panel (Variation ID 54310). ACMG/AMP Criteria applied: BP4_Strong, BS1.
ITMI	RCV000120282	SCV000084434	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111655	SCV000144144	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554651	SCV004735235	likely benign	BRCA1-related disorder	2020-09-09	no assertion criteria provided	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).