Submissions for variant NM_000059.4(BRCA2):c.1322C>T (p.Thr441Ile)

dbSNP: rs1064793062

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483055	SCV000564764	uncertain significance	not provided	2015-02-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1322C>T at the cDNA level, p.Thr441Ile (T441I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 1550C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr441Ile 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 Thr441Ile occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). 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 Thr441Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193992	SCV001363204	uncertain significance	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1322C>T (p.Thr441Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246594 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has been reported in the literature as a somatic occurrence in triple negative breast cancer (Pop_2018) as well as in a patient with HBOC (Santonocito_2020), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525754	SCV003240858	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-12	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 441 of the BRCA2 protein (p.Thr441Ile). 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. 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. ClinVar contains an entry for this variant (Variation ID: 418077). This missense change has been observed in individual(s) with hereditary breast cancer and/or ovarian cancer (PMID: 32438681). This variant is not present in population databases (gnomAD no frequency).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157559	SCV003850001	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).