Submissions for variant NM_000059.4(BRCA2):c.8614G>A (p.Glu2872Lys)

dbSNP: rs1555287788

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564672	SCV000668547	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-20	criteria provided, single submitter	clinical testing	The p.E2872K variant (also known as c.8614G>A), located in coding exon 19 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8614. The glutamic acid at codon 2872 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564672	SCV001340506	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2872 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 reported in 1 individual affected with breast cancer (Color internal data). In a large breast cancer case-control study, this variant was observed in 0/60466 cases and 1/53461 controls (Leiden Open Variation Database DB-ID BRCA2_008685; PMID: 33471991). This variant has not been identified 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.
GeneDx	RCV001824812	SCV002588070	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 8842G>A; This variant is associated with the following publications: (PMID: 12228710, 31911673)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150245	SCV003838841	uncertain significance	Breast and/or ovarian cancer	2021-08-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766811	SCV004669180	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-22	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 2872 of the BRCA2 protein (p.Glu2872Lys). This variant is not present in population databases (gnomAD no frequency). 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: 433827). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504275	SCV000592212	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu2872Lys variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, or BIC databases. The p.Glu2872 residue is conserved across mammals but not lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD) suggest that the p.Glu2872Lys variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
GenomeConnect, ClinGen	RCV001824812	SCV002074567	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.