Submissions for variant NM_000059.4(BRCA2):c.5020A>G (p.Ser1674Gly)

gnomAD frequency: 0.00020  dbSNP: rs80358725

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044539	SCV000072552	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129669	SCV000184467	benign	Hereditary cancer-predisposing syndrome	2015-06-10	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.
GeneDx	RCV000588519	SCV000278855	likely benign	not provided	2023-09-27	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Counsyl	RCV000113368	SCV000488261	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588519	SCV000600620	likely benign	not provided	2023-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218378	SCV000694820	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5020A>G (p.Ser1674Gly) results in a non-conservative amino acid change located in the Fifth BRCA2 repeat domain (IPR002093) of the encoded protein sequence. The BRCA2 repeat region consists of eight repeats (BRC) that are critical for binding to RAD51 (a key protein in DNA recombination repair process), where BRC1-4 and BRC7-8 are highly conserved and participate in Rad51 binding, whereas BRC5 and BRC6 are less well conserved and do not bind to Rad51 (PMID 10551859). 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 3.5e-05 in 1593894 control chromosomes, predominantly at a frequency of 0.00054 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. Although this frequency is not higher than the maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), the homozygous occurrence suggests that the variant could be benign. In addition, this variant has been reported in 3/9884 American women who are older than age 70 and cancer free (in the FLOSSIES database). The variant, c.5020A>G, has also been reported in the literature in individuals affected with breast cancer (example, Borg_2010, Kim_2015, Pal_2015, Bishop_2019, Dorling_2021, deOliveira_2022) or with unspecified personal or family history of breast cancer (example, Pereira_2022). These reports, however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8902dupA, p.Thr2968Asnfs*50), providing supporting evidence for a benign role (deOliveira_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 21520273, 26287763, NOT_FOUND, 31131967, 31415627, 31294896, 33471991, 35980532, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=1), likely benign (n=5), or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000129669	SCV000911691	likely benign	Hereditary cancer-predisposing syndrome	2015-07-16	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044539	SCV002504852	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129669	SCV002533919	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129669	SCV003852286	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113368	SCV000146521	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588519	SCV001955224	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588519	SCV001969647	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732613	SCV005350242	likely benign	BRCA2-related disorder	2024-06-14	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).