Submissions for variant NM_000059.4(BRCA2):c.620C>T (p.Thr207Ile)

gnomAD frequency: 0.00001  dbSNP: rs41293471

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165697	SCV000216436	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.T207I variant (also known as c.620C>T), located in coding exon 6 of the BRCA2 gene, results from a C to T substitution at nucleotide position 620. This alteration has been identified in individuals diagnosed with ovarian and colorectal cancer (Alsop K et al. J. Clin. Oncol., 2012 Jul;30:2654-63; Pearlman R et al. JAMA Oncol 2017 Apr;3(4):464-471). In addition, this variant was identified in a cohort of 4034 individuals representing 12 cancer types (Lu C et al. Nat Commun, 2015 Dec;6:10086) and was reported in 0/60,466 breast cancer cases and in 1/53,461 controls in another large study (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense variant, this alteration is predicted to be tolerated by in silico analysis. In silico splice site analysis for this alteration, however, is inconclusive. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Di Giacomo D et al. Hum. Mutat. 2013 Nov; 34(11):1547-57; Fraile-Bethencourt E. J Pathol. 2019 Aug;248(4):409-420; Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000759634	SCV000279426	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, and other cancers, as well as in unaffected controls (Alsop et al., 2012; Lu et al., 2015; Pearlman et al., 2017; Dorling et al., 2021); Published functional studies are inconclusive: leads to partial exon 7 skipping, producing both full-length and truncated mRNA transcripts (Di Giacomo et al., 2013; Fraile-Bethencourt et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 848C>T; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 26556299, 26976419, 27284491, 23983145, 22711857, 26689913, 20513136, 18724707, 27978560, 30883759, 33471991, 26761715, 29884841)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461512	SCV000549716	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-30	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 207 of the BRCA2 protein (p.Thr207Ile). This variant is present in population databases (rs41293471, gnomAD 0.004%). This missense change has been observed in individual(s) with breast, ovarian or colorectal cancer (PMID: 22711857, 26689913, 27978560). ClinVar contains an entry for this variant (Variation ID: 186155). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759634	SCV000889089	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000035 (4/113644 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast/ovarian cancer (PMIDs: 22711857 (2012), 25186627 (2015), 26689913 (2015)) or colorectal cancer (PMID: 27978560 (2016)). In vitro splicing studies report that this variant interferes with proper BRCA2 mRNA splicing and leads to incomplete skipping of exon 7 (PMIDs: 23983145 (2013), 26761715 (2016), 30883759 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000165697	SCV000911793	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 207 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). RNA assays have shown that this variant results in increased exon 7 skipping (21-55% of transcripts), which occurs at a low level in control cells (11% of transcripts). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22711857, 25186627), colorectal cancer (PMID: 27978560), and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007247). This variant has been identified in 4/251284 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	RCV000214941	SCV000916908	uncertain significance	not specified	2018-03-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.620C>T (p.Thr207Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Two publications report experimental evidence that this missense variant affects mRNA splicing (~42-45% normal transcription products)(DiGiacomo_2013, Soukarieh_2016). The variant allele was found at a frequency of 1.6e-05 in 246108 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.6e-05 vs 7.50e-04), allowing no conclusion about variant significance. c.620C>T has been reported in the literature in individuals affected with Breast, Ovarian, and Colon Cancer (Alsop_2012, Tung_2014, Lu_2015) . These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Sema4, Sema4	RCV000165697	SCV002536210	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-24	criteria provided, single submitter	curation
Baylor Genetics	RCV003462185	SCV004213643	uncertain significance	Familial cancer of breast	2023-11-10	criteria provided, single submitter	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV003483540	SCV004228320	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PP3(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)