Submissions for variant NM_000059.4(BRCA2):c.3731T>C (p.Ile1244Thr)

gnomAD frequency: 0.00001  dbSNP: rs730881526

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586904	SCV000210322	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3959T>C; Observed in at least one individual with triple negative breast cancer (Wong-Brown et al., 2015); This variant is associated with the following publications: (PMID: 16826315, 31911673, 31131967, 34572941, 31853058, 25682074, 32377563, 29884841)
Ambry Genetics	RCV000165364	SCV000216090	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.I1244T variant (also known as c.3731T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3731. The isoleucine at codon 1244 is replaced by threonine, an amino acid with similar properties. This alteration was identified in one individual from a cohort of 774 Australian women with triple-negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat., 2015 Feb;150:71-80). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000165364	SCV000688830	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1244 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007347) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0757 and 0.2148, respectively (PMID: 31131967). This variant has been identified in 2/247518 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586904	SCV000694713	uncertain significance	not provided	2017-05-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.3731T>C (p.Ile1244Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in one of the BRCA2 repeat domains (InterPro). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/119920 control chromosomes), but is identified in gnomAD dataset (2/242492 chrs tested). The variant was identified in a breast cancer patient without strong evidence of pathogenicity (Wong-Brown_BRCA1&2_BCRT_2015). Two clinical diagnostic laboratories have classified this variant as one of uncertain significance. Taken together, this variant is classified as a VUS until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586904	SCV000887795	uncertain significance	not provided	2024-10-17	criteria provided, single submitter	clinical testing	The BRCA2 c.3731T>C (p.Ile1244Thr) variant has been reported in the published literature in an individual with breast cancer (PMIDs: 25682074 (2015) and 34572941 (2021)) and in reportedly healthy individuals (PMIDs: 33471991 (2021), 38566028 (2024); LOVD3 Shared (https://databases.lovd.nl/shared/)). It has also been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)), as well as being likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.0000081 (2/247518 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824375	SCV000965271	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1244 of the BRCA2 protein (p.Ile1244Thr). This variant is present in population databases (rs730881526, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25682074). ClinVar contains an entry for this variant (Variation ID: 182203). 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.
Sema4, Sema4	RCV000165364	SCV002533817	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165364	SCV003846825	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).
All of Us Research Program, National Institutes of Health	RCV003998442	SCV004845212	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1244 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007347) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0757 and 0.2148, respectively (PMID: 31131967). This variant has been identified in 2/247518 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.