Submissions for variant NM_000059.4(BRCA2):c.2186T>C (p.Ile729Thr)

gnomAD frequency: 0.00001  dbSNP: rs431825296

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166578	SCV000217380	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The p.I729T variant (also known as c.2186T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2186. The isoleucine at codon 729 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple Asian breast and/or ovarian and colorectal cancer cohorts, but has also been observed in healthy control patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789; Lai KN et al. BMC Cancer, 2017 02;17:149; Nakagomi H et al. Cancer Sci, 2018 Feb;109:453-461; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Xu Y et al. Front Oncol, 2020 Sep;10:1603; Ha HI et al. J Gynecol Oncol, 2020 Nov;31:e83; Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec). This alteration was also detected in 5/11,386 Chinese Han individuals over 19 years of age without history of cancer (Dong H et al. J Med Genet, 2021 Aug;58:565-569). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240800	SCV000265949	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637814	SCV000759293	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-24	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 729 of the BRCA2 protein (p.Ile729Thr). This variant is present in population databases (rs431825296, gnomAD 0.01%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 27257965, 28222693, 30078507, 30702160, 31248605, 31825140). ClinVar contains an entry for this variant (Variation ID: 96780). 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.
3DMed Clinical Laboratory Inc	RCV000677830	SCV000803990	uncertain significance	Ovarian cancer	2017-04-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758870	SCV000887768	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00022 (4/18388 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 30702160 (2019), 30287823 (2018), 28222693 (2017), 27257965 (2016)), prostate cancer (PMID: 31248605 (2019)), and colorectal cancer (PMIDs: 33078592 (2020), 32984025 (2020)). Additionally, the variant has been reported in healthy individuals (PMIDs: 33471991 (2021)). 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.
Fulgent Genetics, Fulgent Genetics	RCV000763882	SCV000894817	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112184	SCV001269823	uncertain significance	Fanconi anemia complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000082901	SCV001269824	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000166578	SCV001339332	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 729 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 three individuals affected with breast cancer (PMID: 27257965, 28222693) and four healthy control individuals (PMID 28222693). A case-control study in a Japanese population has shown no significant association with colorectal cancer (PMID: 33309985). This variant has been identified in 4/251228 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	RCV002298468	SCV002599064	uncertain significance	not specified	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2186T>C (p.Ile729Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2186T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example Xu_2020, Wei_2019, Zhong_2016, Dorling_2021) as well as multiple healthy control individuals (Li_2018, Lai_2017, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27257965, 30078507, 28222693, 31248605, 32984025, 33471991). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=8) or benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV000677830	SCV003843267	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166578	SCV003846556	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	RCV000082901	SCV004847018	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 729 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 three individuals affected with breast cancer (PMID: 27257965, 28222693) and four healthy control individuals (PMID 28222693). A case-control study in a Japanese population has shown no significant association with colorectal cancer (PMID: 33309985). This variant has been identified in 4/251228 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.
Sharing Clinical Reports Project (SCRP)	RCV000082901	SCV000114975	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing