Submissions for variant NM_000059.4(BRCA2):c.8366A>G (p.Tyr2789Cys)

dbSNP: rs398122603

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206251	SCV000261037	likely benign	Hereditary breast ovarian cancer syndrome	2024-03-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214265	SCV000278341	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The p.Y2789C variant (also known as c.8366A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8366. The tyrosine at codon 2789 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). 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.
Counsyl	RCV000077025	SCV000489594	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214265	SCV000911811	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2789 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature and has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008663). This variant has been identified in 1/251424 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553615	SCV001774535	uncertain significance	not specified	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8366A>G (p.Tyr2789Cys) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8366A>G has been reported in the literature as a VUS of germline origin in at-least one individual with hypodiploid ALL (Zhang_2015) and as a presumed germline variant in the setting of Fibrolamellar hepatocellular carcinoma (Cornella_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800379	SCV002046457	uncertain significance	not provided	2024-11-20	criteria provided, single submitter	clinical testing	The BRCA2 c.8366A>G (p.Tyr2789Cys) variant has been reported in an individual each with acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)), and an individual with Fibrolamellar hepatocellular carcinoma (FLC) (PMID: 25557953 (2015)). This variant has also been identified in a reportedly healthy individual (PMID: 35585550 (2022)). The frequency of this variant in the general population, 0.000004 (1/251424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000077025	SCV004043189	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-17	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].
GeneDx	RCV001800379	SCV005078360	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	Identified in a pediatric patient with hypodiploid acute lymphocytic leukemia (PMID: 26580448); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8594A>G; This variant is associated with the following publications: (PMID: 25557953, 32377563, 29884841, 12228710, 26580448, 31853058)
All of Us Research Program, National Institutes of Health	RCV004804056	SCV005425793	uncertain significance	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2789 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature and has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008663). This variant has been identified in 1/251424 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)	RCV000077025	SCV000108822	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-02-12	no assertion criteria provided	clinical testing