Submissions for variant NM_000059.4(BRCA2):c.3697G>A (p.Ala1233Thr)

gnomAD frequency: 0.00002  dbSNP: rs80358613

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998147	SCV000296537	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The BRCA2 c.3697G>A (p.Ala1233Thr) variant has been reported in the published literature in an individual with biliary tract cancer (PMID: 29416916 (2018)), 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, 0.00015 (5/34100 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.
Color Diagnostics, LLC DBA Color Health	RCV000773261	SCV000906903	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1233 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. This variant has been identified in 6/248936 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001319239	SCV001509977	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1233 of the BRCA2 protein (p.Ala1233Thr). This variant is present in population databases (rs80358613, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51507). 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.
Sema4, Sema4	RCV000773261	SCV002533813	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	curation
Ambry Genetics	RCV000773261	SCV002623989	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	The p.A1233T variant (also known as c.3697G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3697. The alanine at codon 1233 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509189	SCV002819384	uncertain significance	not specified	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3697G>A (p.Ala1233Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248936 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3697G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or 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	RCV000773261	SCV003846803	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).
PreventionGenetics, part of Exact Sciences	RCV004528243	SCV004108504	uncertain significance	BRCA2-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	The BRCA2 c.3697G>A variant is predicted to result in the amino acid substitution p.Ala1233Thr. To our knowledge, this variant has not been reported with BRCA2-related disease in the literature. This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912189-G-A). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/51507/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113208	SCV000146281	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing