Submissions for variant NM_000059.4(BRCA2):c.8515T>C (p.Tyr2839His)

gnomAD frequency: 0.00002  dbSNP: rs758884639

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167960	SCV000218608	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2839 of the BRCA2 protein (p.Tyr2839His). This variant is present in population databases (rs758884639, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806, 35918668). ClinVar contains an entry for this variant (Variation ID: 188108). 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.
GeneDx	RCV000586024	SCV000569757	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8743T>C; This variant is associated with the following publications: (PMID: 27093186, 31131967, 12228710, 29470806, Tria2019[CaseReport], 35918668, 32467295, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000580149	SCV000683977	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 2839 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 an individual affected with breast or ovarian cancer (PMID: 29470806). This variant has also been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 2/53459 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008676). This variant has been identified in 6/251166 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	RCV000586024	SCV000695162	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing	Variant summary: The c.8515T>C (p.Tyr2839His) in BRCA2 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain or repeats, however no studies determining the functional impact of this variant have been conducted and published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 1.649e-05 (2/121308 chrs tested), exclusively in individuals of South Asian descent (0.0001212; 2/ 16508) which does not exceed the maximal expected frequency of a pathogenic allele (0.00075) in this gene. The variant has not, to our knowledge, been reported in affected individuals via published reports and has been cited by one reputable clinical lab as a VUS. Taking together, the variant was classified as VUS.
Ambry Genetics	RCV000580149	SCV001179106	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-11	criteria provided, single submitter	clinical testing	The p.Y2839H variant (also known as c.8515T>C), located in coding exon 19 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8515. The tyrosine at codon 2839 is replaced by histidine, an amino acid with similar properties. This variant was observed in a study of 1010 unrelated Indian individuals diagnosed with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586024	SCV004220611	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 29470806 (2018) and 33471991 (2021)), however, it was also reported in healthy controls (PMIDs: 32467295 (2020) and 33471991 (2021)). The frequency of this variant in the general population, 0.00013 (4/30614 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.
Baylor Genetics	RCV002250583	SCV005059021	uncertain significance	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003493481	SCV005405010	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-09-03	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].
All of Us Research Program, National Institutes of Health	RCV004804778	SCV005425802	uncertain significance	BRCA2-related cancer predisposition	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 2839 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 29470806, 35918668). This variant has also been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 2/53459 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008676). This variant has been identified in 6/251166 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250583	SCV002520843	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV003493481	SCV004243824	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing