Submissions for variant NM_000059.4(BRCA2):c.5939C>T (p.Thr1980Ile)

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Total submissions: 8

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565166	SCV000665991	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	The p.T1980I variant (also known as c.5939C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5939. The threonine at codon 1980 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in an Algerian woman diagnosed with breast cancer at age 40 and no family history of cancer (Henouda S et al. Dis. Markers, 2016 Feb;2016:7869095). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000565166	SCV001348080	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346088	SCV001540261	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-11	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 1980 of the BRCA2 protein (p.Thr1980Ile). This variant is present in population databases (rs80358827, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 12491487, 26997744). ClinVar contains an entry for this variant (Variation ID: 51966). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 36098506). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000565166	SCV003850801	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113506	SCV003932744	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significant was detected . This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1980 of the BRCA2 protein (p.Thr1980Ile). This variant is present in population databases (rs80358827, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 12491487, 26997744). ClinVar contains an entry for this variant (Variation ID: 51966). This amino acid position is highly conserved . In addition, this alteration is predicted to be deleterious and diseases causing by(PolyPhen, BayesDel_addAF, DANN, EIGEN, FATHMMMKL, M-CAP, MVP, MutationTaster and SIFT) . 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.
Breakthrough Genomics, Breakthrough Genomics	RCV004691735	SCV005192113	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV004691735	SCV005201230	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	Identified in an individual with a personal history of breast cancer (PMID: 26997744); Published functional studies demonstrate impaired RAD51-mediated DNA strand exchange and intermediate abilities with respect to cell survival, RAD51 foci formation, and replication fork protection (PMID: 36098506); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6167C>T; This variant is associated with the following publications: (PMID: 31911673, 12491487, 29884841, 32377563, 9002670, 22193408, 37922907, 26997744, 36098506)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113506	SCV000146734	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing

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