Submissions for variant NM_000059.4(BRCA2):c.4277C>T (p.Thr1426Ile)

gnomAD frequency: 0.00001  dbSNP: rs748591104

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000547653	SCV000635357	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-28	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 1426 of the BRCA2 protein (p.Thr1426Ile). This variant is present in population databases (rs748591104, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32101877, 35918668). ClinVar contains an entry for this variant (Variation ID: 462335). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772746	SCV000906079	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1426 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 one individual affected with breast cancer and two unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008184) and in a suspected hereditary breast and ovarian cancer family (PMID: 32380732). This variant has been identified in 2/244798 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985521	SCV001133789	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 32101877 (2019), 35918668 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.0000082 (2/244798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000772746	SCV001183903	likely benign	Hereditary cancer-predisposing syndrome	2019-05-01	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000985521	SCV002501369	uncertain significance	not provided	2021-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000985521	SCV002549582	uncertain significance	not provided	2022-01-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with a personal and family history of breast cancer in published literature (Wu 2019); Also known as 4505C>T; This variant is associated with the following publications: (PMID: 32101877)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772746	SCV003850375	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355495	SCV001550400	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1426Ile variant was not identified in the literature nor was it identified in the COGR, LOVD 3.0, UMD-LSDB, BIC Database, or ARUP Laboratories database. The variant was identified in dbSNP (ID: rs748591104) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 2 of 240852 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), in the following population: East Asian in 2 of 17036 chromosomes (freq: 0.0001), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, or South Asian populations. The p.Thr1426Ile residue is not conserved in mammals and four out of five 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250653	SCV002520788	uncertain significance	Familial cancer of breast		no assertion criteria provided	curation