Submissions for variant NM_000059.4(BRCA2):c.539T>C (p.Ile180Thr)

dbSNP: rs80358761

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044650	SCV000072663	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-03	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 180 of the BRCA2 protein (p.Ile180Thr). This variant is present in population databases (rs80358761, gnomAD 0.0009%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 10923033, 26580448). ClinVar contains an entry for this variant (Variation ID: 51853). 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.
GeneDx	RCV000074539	SCV000108624	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Identified in an individual with family history of pancreatic cancer (Abe 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 767T>C; This variant is associated with the following publications: (PMID: 10923033, 23983145, 32377563, 29884841, 26580448, 26761715, 30883245)
Ambry Genetics	RCV000132009	SCV000187068	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-07	criteria provided, single submitter	clinical testing	The p.I180T variant (also known as c.539T>C), located in coding exon 6 of the BRCA2 gene, results from a T to C substitution at nucleotide position 539. The isoleucine at codon 180 is replaced by threonine, an amino acid with similar properties. A mini-gene splicing assay found that this alteration did not result in aberrant splicing (Di Giacomo D et al. Hum. Mutat. 2013 Nov;34(11):1547-57). This alteration was also identified in an individual diagnosed with pancreatic cancer (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000132009	SCV001354858	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 180 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 detected in an individual affected with pediatric cancer (PMID: 26580448) and an individual considered at risk for pancreatic cancer (PMID: 30883245). This variant also has been reported in a breast cancer meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_003614). This variant has been identified in 1/251410 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262281	SCV001440092	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582540	SCV001821426	uncertain significance	not specified	2021-08-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.539T>C (p.Ile180Thr) 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. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.539T>C has been reported in the literature in at least one individual affected with pediatric cancer (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Splicing assay showed that this variant did not increase exon skipping (Di Giacomo_2013, Soukarieh_2016). Five 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 uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000083116	SCV000115190	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083116	SCV000147092	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing