Submissions for variant NM_000059.4(BRCA2):c.1804G>A (p.Gly602Arg)

gnomAD frequency: 0.00002  dbSNP: rs80358466

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077267	SCV000244426	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 = 0.000000101
Invitae	RCV001081276	SCV000071906	benign	Hereditary breast ovarian cancer syndrome	2024-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001284557	SCV000210569	likely benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24323938, 20104584, 20383589, 21218378, 21990134, 28678401, 21232165, 18559594, 23034506, 17924331, 27300552, 32444794, 32123317)
Ambry Genetics	RCV000162545	SCV000212949	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.
Counsyl	RCV000077267	SCV000488588	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162545	SCV000683452	likely benign	Hereditary cancer-predisposing syndrome	2015-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168552	SCV000694568	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1804G>A (p.Gly602Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 239200 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.1804G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lee_2008, Soegaard_2008, Borg_2010, Balabas_2010, Stegel_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5263_5264insC, p.Ser1755?fs; BRCA1 c.2679_2682delGAAA, p.Lys893_Lys894?fs in the BIC database; BRCA2 c.7558C>T , p.Arg2520Ter in a patient tested at our laboratory), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077267	SCV000743266	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077267	SCV000744418	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284557	SCV001470405	likely benign	not provided	2022-12-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168552	SCV002550290	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077267	SCV000109064	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077267	SCV000145944	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077267	SCV000733235	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168552	SCV001906033	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168552	SCV001953400	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077267	SCV004244233	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing