Submissions for variant NM_000059.4(BRCA2):c.1662T>G (p.Cys554Trp)

gnomAD frequency: 0.00006  dbSNP: rs80358451

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)	RCV000077261	SCV000244423	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 = 0.000000396
Invitae	RCV000167777	SCV000071869	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001703942	SCV000210566	likely benign	not provided	2021-06-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 10464631, 24323938, 17924331, 9654203, 21952622, 22771033, 25637381, 27150160)
Ambry Genetics	RCV000163000	SCV000213488	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: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768621	SCV000219304	uncertain significance	Breast and/or ovarian cancer	2015-10-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000043856	SCV000591759	benign	not specified	2015-12-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703942	SCV000602785	benign	not provided	2022-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043856	SCV000694555	benign	not specified	2020-05-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1662T>G (p.Cys554Trp) 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 5.7e-05 in 282630 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.7e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.1662T>G has been reported in the literature in individuals affected with prostate cancer, breast cancer and ovarian cancer without strong evidence for causality (Kote-Jari_2011, Ganguly_1998, Ganguly_1997). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two studies using multifactorial likelihood models have classified this variant as having a neutral impact (Easton_2007, Lindor_2012) (IARC class I). In addition, although a functional study (Mondal_2012) reports this variant as resulting in increased cytokinetic defects through a disruption of BRCA2 interactions with other proteins, the authors do not report its effect on BRCA2 dependant homologous recombination repair. Therefore, the impact of this study on the pathophysiology and mechanism of cancer has not been fully understood and/or established. At least one co-occurrence of this variant with another likely pathogenic variant has been reported at our laboratory (BRCA2 c.4305_4309delTATTA, p.Asn1435fsX8), providing supporting evidence for a benign role. Nine submitters including one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014, some citing overlapping evidence utilized in the context of this evaluation. Eight submitters including the expert panel have classified the variant as benign (n=5)/likely benign(n=3) while one retains the classification as a VUS. We have followed this variant for over 6 years since its initial identification at our laboratory. Based on the lack on conclusive evidence supporting a pathogenic outcome for this variant in literature spanning over two decades as ascertained above and the emerging majority consensus in the field, the variant was re-classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000163000	SCV000910758	benign	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000077261	SCV001139005	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000043856	SCV002068966	likely benign	not specified	2021-12-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163000	SCV002533250	likely benign	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043856	SCV002550284	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703942	SCV003917267	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
PreventionGenetics, part of Exact Sciences	RCV003904995	SCV004725042	benign	BRCA2-related condition	2019-08-01	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000077261	SCV000109058	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077261	SCV000145909	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148416	SCV000190115	likely benign	Carcinoma of male breast	2014-06-01	no assertion criteria provided	research
True Health Diagnostics	RCV000163000	SCV000886672	likely benign	Hereditary cancer-predisposing syndrome	2018-11-12	no assertion criteria provided	clinical testing