Submissions for variant NM_000059.4(BRCA2):c.5635G>A (p.Glu1879Lys)

gnomAD frequency: 0.00008  dbSNP: rs55996097

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167807	SCV000072715	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129072	SCV000183775	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000755862	SCV000210616	likely benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32426482, 27062684, 28222693, 28263838, 18092194, 24504028, 26689913, 23555315, 20104584, 18627636, 22811390, 16847550, 16760289)
Illumina Laboratory Services, Illumina	RCV000336386	SCV000383719	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000077357	SCV000383720	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168580	SCV000694886	benign	not specified	2020-02-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5635G>A (p.Glu1879Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248816 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer allowing no conclusion about variant significance. c.5635G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer, contralateral breast cancer, and other cancerous settings ((example, Borg_2010, Capalbo_2006, Capanu_2011, Cunningham_2014, Giannini_2006, Haiman_2013, Pennington_2013, Seymour_2008, Thirthagiri_2008, Azzolini_2016, Lai_2017, Zuntini_2018). The variant was reported as not co-segregating with disease in at-least one of these reports (Zuntini_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants in the BRCA2 and BRCA1 genes have been reported in the UMD and the BIC databases respectively in addition to another co-occurrence in the MSH6 gene tested at our laboratory (BRCA2 c.8463dup, p.Ile2822fs; BRCA1 c.5263_5264insC, p.Ser1755?fs, MSH6 c.3733_3739dupTTTTCAA , p.Thr1247fsX30), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some of these submitters cite overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=6). Based on the evidence outlined above, the variant was re-classified from likely benign to benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077357	SCV000744471	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755862	SCV000883488	likely benign	not provided	2017-09-06	criteria provided, single submitter	clinical testing	The p.Glu1879Lys variant has been reported in individuals with breast and/or ovarian cancer; however, inheritance and specific clinical information were not reported (Borg 2010, Pennington 2012, and Thirthagiri 2008). The p.Glu1879Lys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the South Asian population (identified in 7 out of 29,948 chromosomes; 1 homozygote), and is classified as likely benign/benign in ClinVar (Variant ID: 51895). The glutamic acid at codon 1,879 is moderately conserved considering 12 species (Alamut software v2.9.0), and it is a lysine in dogs, suggesting that this change may be evolutionary tolerated. Computational analyses predict that this variant does not affect the BRCA2 protein structure/function (GV/GD: C0, SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Based on the available evidence, the p.Glu1879Lys variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755862	SCV000887853	benign	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129072	SCV000902758	benign	Hereditary cancer-predisposing syndrome	2016-09-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000755862	SCV002010352	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168580	SCV002066579	likely benign	not specified	2019-12-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129072	SCV002536155	likely benign	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129072	SCV003848972	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168580	SCV004027444	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077357	SCV000109154	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-08-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077357	SCV000146649	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077357	SCV000733268	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077357	SCV001553809	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Glu1879Lys variant was identified in 3 of 4882 proband chromosomes (frequency: 0.0006) from Malaysian and American individuals or families with breast or endometrial cancer (Thirthagiri 2008, Pennington 2012, Borg 2010). The variant was also identified in dbSNP (ID: rs55996097) “With Pathogenic, other allele”, ClinVar (conflicting interpretations of pathogenicity: classified as benign by Invitae and SCRP; classified as likely benign by Ambry Genetics, GeneDx, Illumina Clinical Services Laboratory, and two other clinical laboratories; and classified as uncertain significance by BIC, Integrated Genetics/Laboratory Corporation of America, CHEO and Quest Diagnostics Nichols Institute San Juan Capistrano), GeneInsight-COGR (1x), LOVD 3.0 (1x), UMD-LSDB (classified as 3-UV, co-occurring with the pathogenic variant BRCA2 c.8643dup, p.Ile2822Tyrfs*23) and BIC Database (10x, clinical importance unknown, classification pending). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 35 of 274724 chromosomes (1 homozygous) at a frequency of 0.0001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 28 of 125750 chromosomes (freq: 0.0002), and South Asian in 7 (1 homozygous) of 29948 chromosomes (freq: 0.0002), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1879 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000755862	SCV001954563	likely benign	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077357	SCV004228415	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000077357	SCV004243675	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542701	SCV004758691	likely benign	BRCA2-related disorder	2019-12-04	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).