Submissions for variant NM_000059.4(BRCA2):c.9725C>T (p.Thr3242Ile)

dbSNP: rs768210077

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229017	SCV000283373	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3242 of the BRCA2 protein (p.Thr3242Ile). This variant is present in population databases (rs768210077, gnomAD 0.0009%). 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: 236933). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284599	SCV001470468	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298288	SCV003995792	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-04	criteria provided, single submitter	clinical testing	The p.T3242I variant (also known as c.9725C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9725. The threonine at codon 3242 is replaced by isoleucine, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
GeneDx	RCV001284599	SCV004022720	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Observed in an individual with bile duct cancer, suspected of having hereditary breast and ovarian cancer syndrome (Lerner-Ellis et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9953C>T; This variant is associated with the following publications: (PMID: 32377563, 29884841, 32885271)
All of Us Research Program, National Institutes of Health	RCV001357380	SCV004846223	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 3242 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251100 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357380	SCV001552837	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3242Ile variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB databases. The variant was identified in dbSNP (rs768210077) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 1 of 251,100 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 113,586 chromosomes (freq: 0.000009); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Thr3242 residue is not conserved in mammals and 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.