Submissions for variant NM_000059.4(BRCA2):c.10070C>T (p.Thr3357Ile)

gnomAD frequency: 0.00001  dbSNP: rs80358388

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130535	SCV000185404	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.T3357I variant (also known as c.10070C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 10070. The threonine at codon 3357 is replaced by isoleucine, an amino acid with 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.
GeneDx	RCV000212292	SCV000210522	uncertain significance	not provided	2014-08-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.10070C>T at the cDNA level, p.Thr3357Ile (T3357I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed at least once in an individual whose personal and/or family history was presumably suspicious for hereditary breast and ovarian cancer syndrome (Olopade 2003). BRCA2 Thr3357Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr3357Ile occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr3357Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000112834	SCV000784891	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130535	SCV000905839	likely benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779914	SCV000916830	uncertain significance	not specified	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.10070C>T (p.Thr3357Ile) variant involves the alteration of a non-conserved nucleotide that leads to change in an evolutionarily non-conserved amino acid residue that is located at the C-terminal end of the protein that does not belong to any known functional domain. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). In addition, a truncation variant upstream of this position have been observed in the general population (with several homozygous occurrences) and classified as benign by our laboratory and others (c.9976A>T (p.Lys3326Ter)), suggesting that even the complete functional loss of this C-terminal protein part wouldnt lead to deleterious biological effects, though these predictions have not been confirmed by in vitro or in vivo functional studies. This variant was found in 1/30974 control chromosomes at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346739	SCV001540965	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-26	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 3357 of the BRCA2 protein (p.Thr3357Ile). This variant is present in population databases (rs80358388, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51036). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112834	SCV000145746	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing