Submissions for variant NM_000059.4(BRCA2):c.9253A>C (p.Thr3085Pro)

gnomAD frequency: 0.00003  dbSNP: rs397507423

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587457	SCV000523999	likely benign	not provided	2019-10-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28591715)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000439515	SCV000602829	likely benign	not specified	2016-11-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509957	SCV000608022	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing	The p.T3085P variant (also known as c.9253A>C), located in coding exon 23 of the BRCA2 gene, results from an A to C substitution at nucleotide position 9253. The threonine at codon 3085 is replaced by proline, an amino acid with highly similar properties. 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.
Invitae	RCV000557691	SCV000635726	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-20	criteria provided, single submitter	clinical testing	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. This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3085 of the BRCA2 protein (p.Thr3085Pro). This variant is present in population databases (rs397507423, 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: 38224). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587457	SCV000695223	likely benign	not provided	2016-06-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9253A>C (p.Thr3085Pro) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. This variant was found in 1/119814 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been found to co-occur in cis with a pathogenic mutation BRCA2 c.9235delG (p.Val3079PhefsX4) in an LCA sample, suggesting the benign role of the variant. One clinical diagnostic laboratories/reputable databases classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000509957	SCV000908252	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-31	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 3085 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/250264 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	RCV000587457	SCV001133971	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 34196900 (2021)) and in an individual with colorectal cancer (PMID: 28591715 (2017)). The frequency of this variant in the general population, 0.0002 (7/34306 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000557691	SCV002819233	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390708	SCV004119199	uncertain significance	BRCA2-related condition	2022-11-17	criteria provided, single submitter	clinical testing	The BRCA2 c.9253A>C variant is predicted to result in the amino acid substitution p.Thr3085Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954279-A-C). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/38224/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000031807	SCV000054415	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-01-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031807	SCV000592266	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Thr3085Pro variant was not identified in the literature. This residue is not conserved in mammals and the variant residue proline (Pro) is found in opossum, increasing the likelihood this variant does not have clinical significance. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant was identified in the presence of a co-occuring pathogenic variant in this individual, increasing the likelihood this variant is benign. In summary, base on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.