Submissions for variant NM_000059.4(BRCA2):c.1385A>G (p.Glu462Gly)

gnomAD frequency: 0.00020  dbSNP: rs56403624

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031319	SCV000244421	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 = 0.00000293
Invitae	RCV000195299	SCV000071806	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000656588	SCV000210559	likely benign	not provided	2021-05-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10717622, 24504028, 15026808, 21952622, 21520273, 24323938, 19200354, 15172753, 20104584, 19491284, 18451181, 21990134, 17924331, 15695382, 19563646, 16905680, 27616075, 29036293, 32444794)
Ambry Genetics	RCV000162999	SCV000213487	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.
Counsyl	RCV000031319	SCV000220497	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-10	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000173630	SCV000224758	benign	not specified	2014-10-13	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162999	SCV000267014	benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000173630	SCV000301756	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195299	SCV000494425	benign	Hereditary breast ovarian cancer syndrome	2015-08-20	criteria provided, single submitter	clinical testing	Variant Summary: The c.1385A>G variant involves the alteration of a non-conserved nucleotide and 2/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.023%, primarily observed in the European (Non-Finnish) cohort at a frequency of 0.041%. These frequencies do not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant was reported in the literature and databases in individuals who also have pathogenic BRCA1 (n=1) and BRCA2 (n=3) mutations (UMD, BIC, Simard_2007) suggesting a benign nature of the variant. Additionally, the variant was found to not segregate with disease in families tested (3 affected family members did not carry the variant; Gomez Garcia_2009). Functional studies showed the variant performed similarly to wild-type BRCA2 in assays of cellular survival and viability, homologous recombination repair, and genome instability (Wu_2005). Multiple reputable databases and clinical labs all classify the variant as benign/likely benign (Emory Genteics, UMD, ARUP, Ambry Genetics, SCRP, GeneDx, Counsyl) along with publications using multifactorial probability based models (Lindor_2012, Gomez Garcia_2009). All data, including co-segregation, functional assays, co-occurrence and the occurrence of this variant in the control population all support the classification of benign, therefore this variant has been classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000173630	SCV000538483	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple publications classify as VUS/not pathogenic; ExAC: 27/66408 European chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000162999	SCV000683419	likely benign	Hereditary cancer-predisposing syndrome	2015-02-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031319	SCV000743259	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031319	SCV000744410	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031319	SCV001138997	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656588	SCV001148973	benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS3:Supporting, BS4
Genetic Services Laboratory, University of Chicago	RCV000173630	SCV002067783	likely benign	not specified	2021-06-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.1385A>G, in exon 10 that results in an amino acid change, p.Glu462Gly. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the European sub-population (dbSNP rs56403624). The p.Glu462Gly change was reported to co-occur with a pathogenic sequence change in the BRCA2 gene (PMID: 16905680). In addition, this variant was found not to segregate with disease in affected families (PMID: 19200354). The p. Glu462Gly change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu462Gly change. Functional studies reported that this sequence change demonstrates similar protein function to the wild-type allele in assays of cellular survival and viability, homologous recombination repair and genome stability (PMID: 15695382). These collective evidences indicate that this is a likely benign sequence change.
Sema4, Sema4	RCV000162999	SCV002533229	benign	Hereditary cancer-predisposing syndrome	2020-12-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173630	SCV002550277	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031319	SCV000053924	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2006-09-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031319	SCV000145862	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000173630	SCV000591741	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Glu462Gly variant was identified in 16 of 5462 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was absent in 200 control chromosomes from theses studies (Capanu 2011, Farrugia 2008, Hadjisavvas 2003, Hadjisavvas 2004, Simard 2007, van Harssel 2010); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also reported in HGMD, LOVD, UMD (14X as a neutral variant), and the BIC database (37X with unknown clinical importance). This variant was identified in dbSNP (ID: rs56403624) “With non-pathogenic allele”, and at a low frequency (0.0003) in the NHLBI Exome Sequencing Project. This residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional assays assessing cell survival, homologous recombination, centrosome regulation and nuclear localization have found no effect of the variant on normal BRCA2 function (Farrugia 2008, Wu 2005). In addition, five in silico studies predict this variant to be neutral or of little clinical significance (Capanu 2011 21520273, Easton 2007, Farrugia 2008, Lindor 2012, van Harssel 2010). This variant was not found to co-segregate with disease in an assessment of four families (Mohammadi 2009), and Simard (2007) found this variant co-occurring with a known deleterious mutation, increasing the likelihood that this variant does not have functional importance. Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656588	SCV000778645	benign	not provided	2017-04-14	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000173630	SCV001797651	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000173630	SCV001905801	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173630	SCV001959985	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031319	SCV004244215	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing