Submissions for variant NM_000059.4(BRCA2):c.9610A>G (p.Thr3204Ala)

gnomAD frequency: 0.00001  dbSNP: rs80359231

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045865	SCV000073878	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-30	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 3204 of the BRCA2 protein (p.Thr3204Ala). This variant is present in population databases (rs80359231, gnomAD 0.01%). This missense change has been observed in individual(s) with personal and/or family history of BRCA2-related conditions (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 52873). 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.
Ambry Genetics	RCV000213913	SCV000277176	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.T3204A variant (also known as c.9610A>G), located in coding exon 25 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9610. The threonine at codon 3204 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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.
Baylor Genetics	RCV003460632	SCV004213637	uncertain significance	Familial cancer of breast	2023-08-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000114133	SCV004846199	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 3204 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 individuals affected with breast or ovarian cancer (PMID: 21120943). This variant has been identified in 1/251390 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114133	SCV000147673	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353605	SCV000592296	uncertain significance	not provided		no assertion criteria provided	clinical testing