Submissions for variant NM_000059.4(BRCA2):c.599C>T (p.Thr200Ile)

gnomAD frequency: 0.00001  dbSNP: rs587781402

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129253	SCV000184012	likely benign	Hereditary cancer-predisposing syndrome	2020-03-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000168233	SCV000218902	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129253	SCV000903814	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 200 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). A functional study has reported that this variant does not impact BRCA2 protein in homology-directed repair and cisplatin sensitivity assays in Brca2-deficient mouse embryonic stem cells (PMID 29988080). RNA studies have reported partial to no impact on splicing, resulting in the out-of-frame skipping of exon 7 (PMID: 23983145, 26780556). This variant has been detected in at least three individuals affected with breast cancer and in an individual affected with endometrial cancer (PMID: 33471991, 33484353; Leiden Open Variation Database DB-ID BRCA2_000713; Color internal data). This variant has been identified in 1/251382 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.
GeneDx	RCV001577607	SCV001805011	likely benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast and other cancers (Yang 2017, Maillet 2006, Quiles 2016, Zuntini 2018, Santonocito 2020, Vietri 2021); Published functional studies demonstrate retained homology directed repair activity, ability to rescue cell lethality, and discordant results with respect to splicing (Mesman 2018, Quiles 2016, Di Giacomo 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 827C>T; This variant is associated with the following publications: (PMID: 33484353, 32438681, 30254663, 29988080, 28664506, 22144684, 16875939, 21702907, 26913838, 26780556, 26269718, 23983145)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001577607	SCV002010345	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271413	SCV002555814	likely benign	not specified	2022-06-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.599C>T (p.Thr200Ile) 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 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.599C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.2774_2775delCT, p.Ser925TyrfsX10), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Quiles_2016, Mesman_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=3, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Medical and Surgical Sciences, University of Bologna	RCV003483493	SCV004228309	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BS3(Strong)+BP5(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)