Submissions for variant NM_000059.4(BRCA2):c.6772G>A (p.Glu2258Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881549

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585930	SCV000210404	uncertain significance	not provided	2015-12-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6772G>A at the cDNA level, p.Glu2258Lys (E2258K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 7000G>A. While this variant was identified as a de novo finding in a child with an autism spectrum disorder, it has not, to our knowledge, been reported in an individual noted to have a personal or family history of cancer (Neale 2012). BRCA2 Glu2258Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2258Lys occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Glu2258Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000572828	SCV000661305	likely benign	Hereditary cancer-predisposing syndrome	2019-03-08	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585930	SCV000694996	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6772G>A (p.Glu2258Lys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. Glu2258 is not conserved across species and is not located in a known functional domain. This variant was found in 1/120952 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was identified as a de novo occurrence in one patients with ASD, but it is unknown if this family had a history of cancer. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information is available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809521	SCV000949674	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2258 of the BRCA2 protein (p.Glu2258Lys). This variant is present in population databases (rs730881549, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182233). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585930	SCV002046167	uncertain significance	not provided	2021-02-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585930	SCV002545112	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4
MGZ Medical Genetics Center	RCV002288677	SCV002579542	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572828	SCV003847440	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	RCV003493465	SCV004243052	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998447	SCV004834249	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2258 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 not been reported in individuals affected with BRCA2-related cancers, but it has been reported in unaffected individuals (PMID: 30287823, 31214711, 32980694). This variant has been identified in 3/282564 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.
Institute of Immunology and Genetics Kaiserslautern	RCV002288677	SCV005043001	uncertain significance	Familial cancer of breast	2024-04-18	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2_P, described BRCA2 coldspot (PMID:31911673); Variant was found in heterozygous state
Fulgent Genetics, Fulgent Genetics	RCV005008067	SCV005633962	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-01-23	criteria provided, single submitter	clinical testing