Submissions for variant NM_000059.4(BRCA2):c.1744A>C (p.Thr582Pro)

gnomAD frequency: 0.00003  dbSNP: rs80358457

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031334	SCV000244425	benign	Breast-ovarian cancer, familial, susceptibility to, 2	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 = 0.0000224
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079595	SCV000071882	benign	Hereditary breast ovarian cancer syndrome	2025-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162597	SCV000213016	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000031334	SCV000267233	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000758864	SCV000512339	likely benign	not provided	2020-11-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 24323938, 21990134, 12624724, 9971877, 19491284, 15117986, 17301269, 26260725, 22771033, 15168169, 18779604, 27124784, 27383479, 26332594, 28782087, 29202657, 28111427, 30415210, 32426482)
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000422713	SCV000586929	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162597	SCV000683441	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758864	SCV000887756	benign	not provided	2023-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000031334	SCV001139008	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422713	SCV001362933	benign	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1744A>C (p.Thr582Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 250296 control chromosomes, predominantly at a frequency of 0.0032 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1744A>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.505C>T, p.Gln169Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Mondal_2012). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x benign-including one expert panel, 3x likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000162597	SCV002533253	likely benign	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000422713	SCV002761147	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000758864	SCV004703500	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS3:Supporting
All of Us Research Program, National Institutes of Health	RCV000031334	SCV004846956	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031334	SCV000053939	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-08-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031334	SCV000145923	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353982	SCV000591762	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr582Pro variant has been identified in 6 out of 1488 proband chromosomes (frequency 0.004) in Korean, Asian American, and North American individuals or families with breast and pancreatic cancers ( Couch 2007, Haffty 2009, Choi 2004, Kurian 2008). In a study elucidating the function of BRCA2 in whole chromosomal instability seen in BRCA2-deficient tumors, the variant disrupted interactions with associated partners involved in maintaining chromosomal stability but has no effect on BRCA2-dependent homologous recombination repair of DNA damage (Mondal 2012). The variant was identified in dbSNP (ID: rs80358457) “With uncertain significance, untested allele”, in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27 of 120326 chromosomes (frequency: 0.0002) (or 27 individuals from a population of East Asians, and none from European (Non-Finnish), Other, African, Latino, South Asian, or European (Finnish) individuals); and was identified by our laboratory in 3 individuals with breast cancer. The variant was also identified in the Clinvitae database (2X, classifications benign and conflicting interpretations), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic/of no clinical significance), the ClinVar database (reviewed by an expert panel and classified as benign; specifically, classified as benign by ENIGMA, Ambry Genetics and Sharing Clinical Reports Project (SCRP) (derived from Myriad reports), classified as uncertain significance by BIC, and unclassified by Invitae), GeneInsight COGR database (unclassified by a clinical laboratory), the BIC database (7X with unknown clinical importance, classification pending), and UMD (unavailable). The p.Thr582 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Other variants were also reported impacting the same site including c.1744A>G, p.Thr582Ala (BIC reported 3 times with unknown clinical significance) and c.1744A>T, p.Thr582Ser (Myriad reported as a polymorphism - personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250484	SCV002520940	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532432	SCV004717057	likely benign	BRCA2-related disorder	2022-08-15	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).