Submissions for variant NM_000059.4(BRCA2):c.6119T>C (p.Ile2040Thr)

dbSNP: rs876659473

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216340	SCV000275989	likely benign	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467262	SCV000549680	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 231981). 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. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2040 of the BRCA2 protein (p.Ile2040Thr). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589937	SCV000694938	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6119T>C (p.Ile2040Thr) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome, and Ile2040 is not located in a known functional domain of the Breast cancer type 2 susceptibility protein. This variant was absent in 120840 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One clinical lab classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216340	SCV003850951	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).