Submissions for variant NM_000059.4(BRCA2):c.8545A>G (p.Lys2849Glu)

gnomAD frequency: 0.00001  dbSNP: rs80359109

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045552	SCV000073565	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2849 of the BRCA2 protein (p.Lys2849Glu). This variant is present in population databases (rs80359109, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52617). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841, 35736817). 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.
Ambry Genetics	RCV000162806	SCV000213287	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000827098	SCV000600813	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162806	SCV000903961	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2849 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). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29394989, 33609447, 35736817). This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 26287763, 29088781, 33471991; Leiden Open Variation Database DB-ID BRCA2_000345). This variant has been identified in 3/282626 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.
GeneDx	RCV000827098	SCV000968715	likely benign	not provided	2018-04-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508013	SCV002600841	likely benign	not specified	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8545A>G (p.Lys2849Glu) results in a conservative amino acid change located in the Tower domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251218 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8545A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Pal_2013, Alvarez_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.3817C>T, p.Gln1273Ter, BIC database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guidugli_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000077445	SCV004846041	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2849 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). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29394989, 33609447, 35736817). This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 26287763, 29088781, 33471991; Leiden Open Variation Database DB-ID BRCA2_000345). This variant has been identified in 3/282626 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.
Sharing Clinical Reports Project (SCRP)	RCV000077445	SCV000109243	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077445	SCV000147398	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing