Submissions for variant NM_000059.4(BRCA2):c.7628A>G (p.Tyr2543Cys)

gnomAD frequency: 0.00001  dbSNP: rs431825354

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122930	SCV000166188	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2543 of the BRCA2 protein (p.Tyr2543Cys). This variant is present in population databases (rs431825354, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or colon cancer (PMID: 30199306, 33773534, 37306523). ClinVar contains an entry for this variant (Variation ID: 96855). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 30696104, 31721781). 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.
Counsyl	RCV000082976	SCV000488836	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000082976	SCV000575762	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000504525	SCV000593755	uncertain significance	not specified	2015-10-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509648	SCV000608235	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-13	criteria provided, single submitter	clinical testing	The p.Y2543C variant (also known as c.7628A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7628. The tyrosine at codon 2543 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple breast cancer cohorts (Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42; Tariq H et al. Asian Pac J Cancer Prev, 2021 Mar;22:719-724; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This alteration also demonstrated no effect on BRCA2/DSS1 binding in one functional study (Caleca L et al. Cancers (Basel), 2019 Jan;11). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000509648	SCV000683896	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2543 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). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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	RCV000758949	SCV000887917	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The BRCA2 c.7628A>G (p.Tyr2543Cys) variant has been reported in individuals affected with breast cancer (PMIDs: 33471991 (2021), 30199306 (2018), see also LOVD (http://databases.lovd.nl/shared)) and ovarian cancer (PMID: 35864222 (2022). Published functional studies have reported inconclusive findings on the effect of this variant on BRCA2 protein function (PMIDs: 30696104 (2019), 31721781 (2019)). The frequency of this variant in the general population, 0.0002 (6/30596 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000765136	SCV000896362	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000758949	SCV001764796	uncertain significance	not provided	2023-12-31	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history of breast or ovarian cancer (PMID: 30199306, 34271787, 33471991); Published functional studies are inconclusive: proficient binding to DSS1, increased relative mRNA expression and radial chromosome formation similar to wildtype, but reduced relative viability of cells following treatment with mitomycin C (PMID: 30696104, 31721781); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7856A>G; This variant is associated with the following publications: (PMID: 30696104, 31721781, 34271787, 33773534, 30199306, 33471991, 12228710, 32720237, Al-AliA2023[preprint])
Sema4, Sema4	RCV000509648	SCV002531877	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000082976	SCV002761584	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504525	SCV003844375	uncertain significance	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7628A>G (p.Tyr2543Cys) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) 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 3.2e-05 in 250888 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7628A>G has been reported in the literature as a VUS in individuals affected with breast cancer (example, Abulkhair_2018, Tariq_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication reports experimental evidence evaluating an impact on protein function with no impact on BRCA2/DSS1 binding, however the data as presented does not allow convincing conclusions about the variant effect (Caleca_2019). Multiple 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000082976	SCV003932756	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	a point mutation in the BRCA2 gene (c.7628A>G (p.Tyr2543Cys)) which results in the substitution of cysteine for tyrosine at amino acid position 2543. This mutation is considered as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004529873	SCV004113298	uncertain significance	BRCA2-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	The BRCA2 c.7628A>G variant is predicted to result in the amino acid substitution p.Tyr2543Cys. This variant has been reported in individuals with breast cancer (Abulkhair et al. 2018. PubMed ID: 30199306; Tariq et al. 2021. PubMed ID: 33773534). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32931889-A-G) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96855/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003474687	SCV004211905	uncertain significance	Familial cancer of breast	2023-10-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000758949	SCV004234655	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492434	SCV004240354	uncertain significance	Breast and/or ovarian cancer	2022-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804090	SCV004844446	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2543 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). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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)	RCV000082976	SCV000115050	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	RCV000082976	SCV004228439	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP4(Supporting) 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)