Submissions for variant NM_000059.4(BRCA2):c.4825A>G (p.Thr1609Ala)

dbSNP: rs876659201

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220835	SCV000275386	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-07	criteria provided, single submitter	clinical testing	The p.T1609A variant (also known as c.4825A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4825. The threonine at codon 1609 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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	RCV000459523	SCV000549752	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1609 of the BRCA2 protein (p.Thr1609Ala). This variant is not present in population databases (gnomAD no frequency). 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: 231512). 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 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	RCV000220835	SCV000683654	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763889	SCV000894824	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283927	SCV001469433	uncertain significance	not provided	2020-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001283927	SCV001790013	uncertain significance	not provided	2022-06-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5053A>G
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150125	SCV003838161	uncertain significance	Breast and/or ovarian cancer	2022-01-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220835	SCV003852126	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358220	SCV001553894	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1609Ala variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs876659201) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Color and Ambry Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Thr1609 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.