Submissions for variant NM_000059.4(BRCA2):c.3667C>T (p.His1223Tyr)

gnomAD frequency: 0.00001  dbSNP: rs786203756

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167201	SCV000218038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-29	criteria provided, single submitter	clinical testing	The p.H1223Y variant (also known as c.3667C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3667. The histidine at codon 1223 is replaced by tyrosine, an amino acid with similar 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 medulloblastoma (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000412156	SCV000489517	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535786	SCV000635298	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1223 of the BRCA2 protein (p.His1223Tyr). This variant is present in population databases (rs786203756, gnomAD 0.009%). This missense change has been observed in individual(s) with medulloblastoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 187469). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167201	SCV000906067	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1223 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 medulloblastoma (PMID: 26580448). This variant has been identified in 3/250018 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	RCV000780008	SCV000916999	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3667C>T (p.His1223Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250018 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3667C>T has been reported in the literature in individuals affected with Medulloblastoma (Zhang_2015) or Anaplastic Astrocytoma (Muskens_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31970404, 26580448). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167201	SCV003846779	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV004804772	SCV004845196	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1223 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 medulloblastoma (PMID: 26580448). This variant has been identified in 3/250018 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	RCV004998357	SCV005624403	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	The BRCA2 c.3667C>T (p.His1223Tyr) variant has been reported in the published literature in individuals with medulloblastoma (PMID: 26580448 (2015)), Astrocytoma (PMID: 31970404 (2020)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000087 (3/34362 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.