Submissions for variant NM_000059.4(BRCA2):c.2755G>A (p.Glu919Lys)

gnomAD frequency: 0.00001  dbSNP: rs431825298

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000082903	SCV001161611	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	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 = 9.62E-06
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231119	SCV000283193	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571395	SCV000668557	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-26	criteria provided, single submitter	clinical testing	The p.E919K variant (also known as c.2755G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2755. The glutamic acid at codon 919 is replaced by lysine, an amino acid with similar properties. One study detected this alteration in a cohort of 167 Croatian women with personal and/or family history of breast and/or ovarian cancer (Levanat S et al. Gene, 2012 May;498:169-76). This alteration has also been detected in 1/1045 Italian breast and/or ovarian cancer patients (Zuntini R et al. Front Genet, 2018 Sep;9:378). This alteration was also classified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons, MT et al. Hum Mutat 2019 Sep;40(9):1557-1578), This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571395	SCV000906049	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 919 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002552) and reported in a suspected hereditary breast and ovarian cancer family (PMID: 22366370). A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.0003, 1.1236, 1.0246 and 1.3654, respectively (PMID: 31131967). This variant has been identified in 3/250712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985487	SCV001133724	likely benign	not provided	2020-09-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000082903	SCV001139040	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000985487	SCV002512813	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer (Levanat 2012, Zuntini 2018, Yildiz Tacar 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2983G>A; This variant is associated with the following publications: (PMID: 22366370, 23929434, 24504028, 30254663, 31131967, 32846166)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271404	SCV002555815	uncertain significance	not specified	2022-06-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2755G>A (p.Glu919Lys) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250712 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2755G>A has been reported in the literature in several individuals affected with personal and/or family history of breast / ovarian cancer (Levanat_2012, Zuntini_2018, Scarpitta_2019, Yildiz Tacar_2020, Dorling_2021, Bandeira_2021). These reports 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 (CHEK2 c.1100delC (p.Thr367Metfs*15) in the LOVD database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 mostly without evidence for independent evaluation, and classified the variant as VUS (n=4), likely benign (n=2), while the expert panel called it benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000082903	SCV004186067	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV004804079	SCV005424345	uncertain significance	BRCA2-related cancer predisposition	2024-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 919 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002552) and reported in a suspected hereditary breast and ovarian cancer family (PMID: 22366370). A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.0003, 1.1236, 1.0246 and 1.3654, respectively (PMID: 31131967). This variant has been identified in 3/250712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV004804079	SCV005914284	uncertain significance	BRCA2-related cancer predisposition	2019-12-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000082903	SCV000114977	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000082903	SCV004228390	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Very Strong) 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	RCV000082903	SCV004244249	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing